The Cornea CHAPTER 6

Anatomy and Physiology of Cornea...... 117 Pathological Changes in Cornea...... 120 Symptoms of Corneal Diseases...... 124 Evaluation of Corneal Diseases...... 124 Inflammation of Cornea...... 127 Corneal Degenerations...... 154 Corneal Dystrophies...... 156 Ectatic Conditions of Cornea...... 161

▄▄Anatomy and Physiology Epithelium of Cornea It may be regarded as continuation of conjunctiva Cornea is avascular and transparent. Its hori­ over cornea. Embryologically, it is derived from zontal and vertical diameters are 12 mm and surface ectoderm at 5 to 6 weeks of gestation. 11.5 mm, respectively (Fig. 6.1). Its thickness at Characteristic features of epithelium are as the center and periphery is 0.5 mm and 0.7 mm, follows: respectively. Radius of curvature of anterior •• It is stratified and 4 to 6 cell layers thick. surface of cornea (in central region) is 7.8 mm, •• The epithelial cells contain microvilli with while that of posterior surface is 6.5 mm. Its glycocalyx layer which facilitate adsorption refractive index is 1.376 (≈1.38). Cornea provides of mucinous portion of tear film and 3/4th of the total refractive power of the eye. Refractive power of anterior convex surface of cornea is +48.8 D; refractive power of posterior concave surface is −5.8 D, so the total refractive power of cornea is 43.0 D. The junction of cornea with sclera is called limbus. The corneal curvature is greater than the rest of the globe. Cornea is devoid of lymphatic channels. 12 mm ██ Histology Histologically, cornea consists of five layers (Fig. 6.2): 1. Epithelium (anterior most). 11.5 mm 2. Bowman’s membrane. 3. Stroma or substantia propria. 4. Descemet’s membrane. 5. Endothelium (posterior most). Fig. 6.1 Diameters of cornea. 118 Chapter 6

Glycocalyx layer

Surface cells Microvilli Wing cells Corneal epithelium Basal cells Basement membrane

Bowman’s membrane

Epithelium Bowman’s membrane

Stroma

Descemet’s membrane Endothelium

Anatomy of cornea Fig. 6.2 Anatomy of cornea.

hydrophilic spreading of tear film with each of new corneal epithelium. Junctional eyelid blink. Loss of glycocalyx from injury or barrier prevents conjunctival tissue from disease results in loss of stability of tear film. growing on the cornea. So, dysfunction or •• Superficial cells undergo desquamation deficiency of limbal stem cells results in the and are replaced by deeper cells of corneal following chronic epithelial defects: epithelium. Basal cells are the only corneal šš Overgrowth of conjunctival epithelium epithelial cells capable of mitosis. Because onto the corneal surface. of excellent ability to regenerate, epithelium šš Vascularization. does not scar as a result of inflammation. These problems can be treated by limbal cell •• Tight junctions between its cells provide transplantation. barrier function and restrict entry of tears into intercellular spaces. Thus, healthy Bowman’s Membrane epithelial surface repels dyes such as It is an acellular structure which, once destroyed, fluorescein or Rose Bengal. does not regenerate. •• Epithelial regeneration: Epithelial stem cells (undifferentiated pluripotent cells) Stroma (Substantia Propria) are principally localized to limbal basal Stroma forms 90% of total corneal thickness. epithelium and serve as an important source It may be regarded as forward continuation of The Cornea 119 sclera. It is composed of collagen fibrils, forming ██ Blood Supply of Cornea lamellae which are loosely adherent to each other Normal cornea is an avascular tissue which gets and regularly arranged in many layers. The layers its nourishment from: crisscross at approximately right angles to each •• Capillaries at limbus which are derived other. Corneal lamellae become continuous with from episcleral branches of the anterior scleral lamellae at limbus. The layered structure of ciliary arteries. stroma results in corneal splitting, as in superficial •• Aqueous by diffusion. keratectomy. Ground substance occupies the space •• Oxygen dissolved in tear film. in between lamellae and is composed of glyco­ saminoglycans (mucopolysaccharides). Corneal ██ Nerve Supply of Cornea cells and keratocytes are found between lamellae Cornea is supplied by the ophthalmic division which are collagen-producing fibroblasts. Corneal of the trigeminal nerve (v ) through long ciliary stroma is markedly hydrophilic due to osmotic force 1 nerves (Fig. 6.4). of stromal glycosaminoglycans (GAG). Course Descemet’s Membrane Long ciliary nerves pierce sclera posterior to It is a thin elastic membrane secreted by limbus and form annular plexus (pericorneal endothelium throughout life. It is composed of plexus). Branches from annular plexus travel collagen fibrils and separates corneal stroma from radially to enter the corneal stroma and lose their endothelium. Unlike Bowman’s membrane, it can myelin sheaths. They divide into anterior group, regenerate (regenerated by endothelial cells). It is which forms subepithelial plexus, and posterior quite resistant to inflammatory process of cornea. group, which forms stromal plexus. Branches Therefore, descematocele can maintain integrity from subepithelial plexus pierce Bowman’s of eye for long after all other layers of cornea are membrane to form intraepithelial plexus. Due destroyed. It fuses with trabecular meshwork. to rich nerve supply, cornea is extremely sensitive The fusion site is known as Schwalbe’s line which structure. In eyes with corneal abrasions or defines the end of Descemet’s membrane and bullous keratopathy, direct stimulation of these start of the trabecular meshwork. nerve axons causes pain, reflex lacrimation, and Endothelium photophobia. It is derived from neural crest cells. It consists of ██ Metabolism of Cornea single layer of flat hexagonal cells and appears Energy is needed for normal functions of a tissue. as honey comb mosaic (Fig. 6.3). It contains a high-density of Na+–K+ ATPase pump. It secretes In cornea, energy is needed for maintenance of its Descemet’s membrane throughout life. It cannot regenerate but adjacent cells slide to fill in a damaged area. Endothelial cell density decreases with advancing age and declines from 3,000– 4,000 cells/mm2 to 2,500 cells/mm2 in adults. At a cell density of approximately 500 cells/mm2, corneal edema develops. It is examined by a specular microscope. The primary physiological role of endothelium is fluid regulation in corneal stroma. This function Fig. 6.3 Honey comb mosaic appearance of endo­ is most important as it keeps the cornea clear. thelium of cornea. 120 Chapter 6

Fig. 6.4 Nerve supply of Pericorneal plexus cornea. (annular plexus) Long ciliary nerve

Subepithelial plexus 1st division of Intraepithelial trigeminal nerve plexus Stromal plexus

Corneal epithelium Bowman’s membrane

Corneal stroma Corneal endothelium

Glucose

Glycolysis ~ 2 ATP generated

Aerobic conditions Pyruvic acid (Via Kreb cycle) under anaerobic conditions O2 H2O

~36 ATP generated per mol of Lactic acid is produced by glucose (Corneal metabolism) corneal epithelium

Stromal changes result due to excess lactic acid

Flowchart 6.1 Metabolism of cornea. Abbreviation: ATP, adenosine triphosphate.

transparency and dehydration. Energy in the form If access of O2 to epithelium is abolished by tight contact of adenosine triphosphate (ATP) is generated by lenses or replacement of air in goggles with N2, cornea breakdown of glucose and utilization of oxygen swells and become cloudy due to production of lactic acid by corneal epithelium under anaerobic conditions. (Flowchart 6.1). Source of glucose for cornea is aqueous (90%), ▄▄Pathological Changes in tears and limbal capillaries (10%). Cornea Source of oxygen for cornea—Most of the The pathological changes in cornea can be O2 in cornea is consumed by epithelium and endothelium. Epithelium gets much of its O2 categorized in (Table 6.1) as follows: from limbal capillaries or precorneal tear film. •• Loss of transparency (corneal edema and

Endothelium gets most of its O2 from aqueous corneal opacity). humor, and the cornea is mainly aerobic. •• Vascularization of cornea. The Cornea 121

•• Integrity of endothelium and epithelium: Table 6.1 Difference between normal and pathological cornea Damage to epithelium or endothelium due to any cause results in corneal swelling Normal cornea Pathological cornea and loss of transparency. However, damage Transparent Loss of transparency due to endothelium is far more serious which to corneal edema and corneal opacity can occur during intraocular surgery/ postuveitis. Avascular Vascularization of cornea •• Corneal endothelial Na+–K+ ATPase pump Absence of pigments Corneal pigmentation and intracellular carbonic anhydrase pathway in endothelium: Activity in both these pathways produces a net flux from •• Pigmentation of cornea. stroma to aqueous. Inhibition of endothelial •• Corneal filaments. Na+–K+ ATPase pump, as in Fuch’s endothelial •• Prominent corneal nerves. dystrophy, leads to corneal edema. •• Infiltrates. If edema lasts for a long period, epithelium is raised into large vesicles or bullae (vesicular or ██ Transparency of Cornea (OP4.3, 4.5) bullous keratopathy). Bullae periodically burst and Normal cornea is a transparent structure. Corneal symptoms like ocular pain and irritation occur. transparency occurs due to regular arrangement Clinical Features of collagen fibrils (corneal lamellae) in stroma, avascularity of cornea and relative state of Corneal edema presents with symptoms like dehydration. Water content of normal cornea is impairment of vision, photophobia, watering, approximately 78%. It is maintained at a steady ocular discomfort, pain due to periodic rupture of level by a balance between various factors. bullae, and halos around light. Disturbance of any of these factors leads to On slit lamp examination, corneal thickness is corneal edema. increased with haze. Epithelial edema is visible on retroillumination with slit lamp. Corneal Edema (OP4.3, 4.5) Management It is the accumulation of fluid in the cornea. It includes: Corneal edema may be epithelial or stromal and •• Treatment of primary causes such as can affect the entire cornea. lower­ing of IOP, and control of ocular Factors Leading to Corneal Edema inflammation. Following factors are responsible for the •• Protection of endothelium during intra­ development of corneal edema: ocular surgery by use of viscoelastics. •• Stromal GAG: Osmotic force of stromal GAG •• Hypertonic agents: plays a role in hydration. Accumulation of GAG šš 5% sodium chloride eye drops × QID. in the cornea (as in Mucopolysaccharidoses) šš 6% sodium chloride eye ointment at bed leads to corneal edema. time. •• Intraocular pressure (IOP): Raised IOP šš Anhydrous glycerine. (≥50 mm Hg) often results in corneal •• Bandage (therapeutic) contact lens to min­ edema due to easy passage of aqueous imize discomfort of bullous keratopathy. through corneal stroma but its escape is •• Penetrating keratoplasty (corneal trans­ retarded by epithelium and accumulation plant) is done in long-standing corneal of fluid in basal cells of epithelium results edema which is nonresponsive to medical in epithelial edema. treatment. 122 Chapter 6

Prognosis Nebular corneal opacity may be so faint that it could be missed on routine examination. A corneal It depends on the status of corneal endothelium. opacity in pupillary area causes blurring of vision. If endothelium is healthy, edema usually resolves •• If iris becomes adherent to the back of completely. Corneas with reduced endothelial cell leucoma in perforated corneal ulcer, it is counts may not be able to recover. called adherent leucoma. Corneal Opacity (OP4.5) •• In a sloughing corneal ulcer, where the whole cornea sloughs, prolapse of Corneal opacity occurs in the epithelial breech that iris occurs. Exudates which cover the involves Bowman’s membrane (Fig. 6.5). It may prolapsed iris become organized and be congenital due to developmental anomalies form a layer of fibrous tissue over which or birth trauma. The common causes include corneal epithelium rapidly grows, resulting infection, injury or corneal abrasion. Corneal in the formation of pseudocornea. More opacification (loss of transparency) may follow commonly, iris and cicatricial tissue are the noninflammatory diseases or inflammation. too weak to support the IOP. Cicatrix (scar) The term “scar” is reserved for the opacity becomes ectatic. Ectasia of pseudocornea following inflammation. Scar tissue is white and with incarceration of iris tissue is known as opaque, and varies in density. anterior staphyloma.

Based on the density of scarring, corneal Bowman’s membrane does not regenerate. So, some opacity may be nebular, macular or leucomatous opacity always remains when Bowman’s membrane has been destroyed. (Table 6.2).

a b Fig. 6.5 Corneal opacity. (a) Macular grade. (b) Leucoma grade.

Table 6.2 Types of corneal opacities

Nebular corneal opacity Macular corneal opacity Leucomatous corneal opacity (nebula) (macula) (leucoma)

Density Less dense + Moderately dense ++ Very dense +++ Involves Bowman’s membrane and Less than half the thickness More than half the superficial stroma of corneal stroma thickness of corneal stroma Structure seen through Details of iris can be seen Details of iris cannot be Obscures view of iris and opacity through opacity seen through opacity pupil The Cornea 123

Treatment •• Deep corneal ulcers. • The ideal procedure either involves • Disciform keratitis. • •• Excimer laser PTK (phototherapeutic • Sclerosing keratitis. • keratectomy), or • Interstitial keratitis (IK). •• Corneal transplantation (keratoplasty). Once the cornea has been vascularized, the vessels remain throughout life, but these blood ██ Vascularization of Cornea (OP4.5) vessels may become empty (“ghost vessels”) Normal cornea is avascular. Vascularization of when stimulus is eliminated. cornea is always pathological. Vascularization, Treatment which is considered as a defence mechanism (immunological defence) against disease, Vascularization can be prevented by timely and interferes with corneal transparency. It may be adequate treatment of predisposing conditions. superficial or deep. Treatment is usually unsatisfactory. The following treatment regimens may be effective: Superficial Vascularization •• Topical corticosteroid causes vasoconstric­ It arises from conjunctival superficial vascular tion and decrease in permeability of vessels. plexus. The vessels are wavy and lie in the •• Beta irradiation. epithelial layer. Continuity of vessels can be •• Peritomy is the surgical treatment of super­ traced with conjunctival vessels at the limbus. It ficial vascularization in intractable cases. is seen in the following: ██ •• Trachoma. Pigmentation of Cornea (OP4.5) •• Phlyctenular keratoconjunctivitis. Pigments deposited may be iron, silver, gold, •• Superficial corneal ulcers. copper, melanin, etc. •• Rosacea keratitis. •• Contact lens wearers. Deposition of Iron Pannus In hyphema (blood in anterior chamber), hemosiderin becomes embedded in the corneal When superficial vascularization is associated stroma. Rise of IOP promotes blood staining with cellular infiltration, it is termed as pannus. of cornea. Blood staining of cornea simulates It may either be progressive when infiltration is dislocation of lens in the anterior chamber. ahead of vessels, or regressive, when infiltration is behind the vessels, that is, infiltration recedes. In keratoconus, deposition of iron hemosiderin Pannus may be located superiorly, inferiorly, or surrounds the base of the cone in the corneal generalized. Superior pannus occurs in trachoma epithelium (Fleischer’s ring). and contact lens wearers. Inferior pannus is In pterygium, iron is deposited as a golden brown associated with exposure keratopathy and line in front of its head (Stocker’s line) in the rosacea. Generalized pannus may be seen in corneal epithelium. chemical burns, Stevens–Johnson syndrome, and In filtering bleb, iron is deposited anterior to Mooren’s ulcer. the filtering bleb (Ferry’s line) in the corneal Deep Vascularization epithelium. It arises from anterior ciliary vessels. The vessels In old age, deposition of iron is seen as a brown run a fairly straight course and lie in the corneal horizontal line (Hudson–Stahli line) in the stroma. The continuity of vessels cannot be traced corneal epithelium. It is located at the junction beyond the limbus. It is seen in the following: of the upper 2/3rd and 1/3rd along the line of lid •• Chemical burns. closure. 124 Chapter 6

Deposition of Silver ██ Corneal Filaments Prolonged topical use of silver nitrate causes These are the epithelial threads attached to cornea impregnation of salt in the stroma and Descemet’s at one end, and the other unattached end is often membrane, resulting in brownish discoloration of club-shaped. These hang over the cornea and Descemet’s membrane (Argyrosis). move freely with each blink, thereby producing irritation and foreign body sensation. Deposition of Copper When a copper foreign body is retained in the eye, ██ Prominent Corneal Nerves deposition of copper occurs around the periphery These may be associated with—Local ocular of the cornea in the region of Descemet’s disorders, for example, membrane and deeper stroma. A gray–green or •• Keratoconus. golden–brown pigmentation of the peripheral •• Acanthamoebic keratitis. corneal stroma is produced (Chalcosis). •• Fuch’s endothelial dystrophy. In Wilson’s disease (hepatolenticular degen­ •• Congenital glaucoma. eration), deposition of copper in the periphery Systemic diseases, for example, of Descemet’s membrane is seen as a golden- •• Neurofibromatosis. brown or green ring just inside the limbus when •• Refsum syndrome. examined on slit lamp (Kayser–Fleischer ring, Fig. 6.6). ██ Infiltrates If viewed in cobalt blue light, the ring appears These originate from the limbal vascular arcades almost black. The condition is reversible with and are indicative of active inflammation. These time, if the disease is treated with penicillamine. are located usually within the anterior stroma and appear as focal, granular, gray–white opacities. Deposition of Melanin These are composed of leucocytes and cellular In pigment dispersion syndrome, uveal pigment debris. (melanin) is deposited on the corneal endothelium in the form of a vertical spindle (Krukenberg’s ▄▄Symptoms of Corneal Diseases spindle). The spindle may be associated with Symptoms of corneal diseases include pain or pigment dispersion glaucoma. slight irritation, visual impairment, lacrimation Deposition of Gold (excessive tear production), photophobia, halos, redness, and foreign body sensation. Specific Gold is deposited in the epithelium in patients symptoms pertaining to different pathologies of with chrysiasis. cornea are listed in Table 6.3.

▄▄Evaluation of Corneal Diseases

Corneal examination can be done with the following: •• Slit lamp. •• Placido’s disc. •• Pachymeter. Fig. 6.6 Kayser Fleischer ring (deposition of •• Corneal staining. copper). Source: Wilson disease (hepatolenticular •• Specular microscopy. degeneration). In: Biousse V, Newman N, ed. Neuro- •• Confocal microscopy. ophthalmology illustrated. 3rd Edition. Thieme; 2019. •• Corneal aesthesiometer. The Cornea 125

Table 6.3 Corneal pathology and symptoms

Corneal pathology Symptoms

•• Corneal abrasions or bullous keratopathy, •• Lacrimation. resulting in direct stimulation of bare nerve •• Pain. endings •• Photophobia associated with reflex blepharospasm because of corneal irritation. The reflex blepharospasm is not completely abolished in dark but is greatly diminished by anaesthetization. •• Loss of central corneal transparency due to: Visual impairment. šš Stromal edema šš Corneal opacity •• Epithelial edema resulting in diffraction of light Halos around light with blue end of spectrum nearest to light source. •• Corneal foreign body or corneal filaments Foreign body sensation.

Cornea is examined for the following: Corneal topography: It is computerized video 1. Size keratography. It provides an objective record of •• Normal size: Horizontal diameter 12 mm the condition of anterior corneal surface (optical and vertical diameter 11.5 mm. and anatomical condition) in the form of color- •• Megalo­cornea (increased size): It may be coded maps. congenital and due to buphthalmos. Green color represents normal curvature. •• Microcornea (decreased size): It may occur Blue color represents flat curvature. isolated­ or as a part of microphthalmos­ (small eye). Red color represents steep curvature.

2. Shape: It is important in preoperative evaluation for •• Normal cornea: It is like a part of a sphere. refractive surgery, for example, in patient with •• Flat cornea (cornea plana): It may occur keratoconus, refractive surgery is deferred. congenitally or in phthisis bulbi. Orbscan is an improved technology which uses •• Conical cornea: In keratoconus. scanning slit technology with Placido disc. It •• Globular cornea: In Keratoglobus. provides information regarding curvature of 3. Surface: Corneal surface and curvature anterior and posterior surfaces of cornea, and can be evaluated by slit lamp, Placido’s disc, depth of anterior chamber. Curvature of anterior Placido keratoscope, corneal topography, and surface of cornea can also be measured by a keratometer. keratometer.

Placido’s keratoscopic disc: Kerato means cornea 4. Transparency: Cornea is optically transparent, and scopic means visualization. The corneal and it becomes hazy in corneal edema, ulcers, surface is visualized by a disc painted with opacity, vascularization, dystrophies and alternating black and white circles and contains a degenerations, and corneal deposits. The hole in the center. Light is kept behind the patient examination for corneal edema and corneal and the examiner looks at corneal image of circles opacity is carried out with the help of a slit lamp. through the hole. The corneal opacity is examined for its density (nebular, macular, or leucomatous), sensations, Uniform and sharp image of circles is seen in location, and its size. normal cornea, while irregularities in rings are seen if corneal surface is uneven as in keratoconus, If keratitis (ulcerative or nonulcerative) is keratoglobus, and corneal astigmatism. suspected, corneal staining is performed. 126 Chapter 6

5. Corneal Staining: Staining of cornea with vital •• Touching cornea with wisp of cotton wool— dyes (Fluorescein or Rose Bengal, Table 6.4) is Normally, there is brisk blink reflex as a important in evaluating corneal epithelial lesions. response. It should be performed before corneal sensation is •• Corneal aesthesiometer provides a more tested and also prior to measurement of IOP. qualitative measurement of corneal sen­ sations. In aesthesiometer, a single horse Alcian blue dye stains mucus selectively, so it stains excess mucus, as in keratoconjunctivitis hair of varying length is used. The longest length which induces blinking is a measure sicca (KCS). of the threshold of corneal sensitivity. In a geographical herpetic ulcer, peripheral devitalized Normally, the cornea is most sensitive in cells are stained with Rose Bengal dye, while the the center. base of the ulcer (epithelial defect) is stained with Fluorescein dye. Corneal sensations are diminished in the following: 6. Corneal Vascularization: The normal cornea •• Herpetic keratitis. is avascular. If corneal vascularization­ is present, •• Neuroparalytic keratitis. note the following points: •• Absolute glaucoma. •• Whether the vessels are superficial or deep. •• Cerebellopontine angle tumor. •• Whether the distribution is localized, •• Leprosy. circumferential, or peripheral. •• Trigeminal block for neuralgia. 7. Corneal Thickness (Pachymetry): Corneal 9. Endothelial Function: Corneal endothelium thickness indirectly reflects endothelial function. can be examined by specular microscopy or It is measured by with the help of the pachymeter. confocal microscopy on a slit lamp. Average corneal thickness at center, that is, Specular microscopy: Specular microscope photo­ central corneal thickness (CCT) is about 0.5 mm graphs the endothelial cells and enables the study (490–560 µm). CCT of ≥0.6 mm is suggestive of their morphology (their number [count], size of endothelial disease. At periphery corneal and shape). thickness is ≈ 0.7 mm. Average cell count is 2,500 cells/mm2. In adults, it CCT can alter measurement of IOP: Patients with declines with age from 3,500 cells/mm2 in children increased CCT record high IOP, while patients to 2,000 cells/mm2 in old age. There is a certain with decreased CCT record low IOP. amount of endothelial cell loss after intraocular 8. Corneal Sensitivity: Cornea is richly supplied surgery. Intraocular surgery is deferred in by nerves. Corneal sensitivity can be tested by: endothelial cell count cases of <1,000 cells/mm2.

Table 6.4 Difference between Fluorescein and Rose Bengal dyes

Fluorescein dye 2% Rose Bengal dye 1%

•• It remains extracellular and does not stain mucus. •• It stains mucus as well as devitalized (dead and It stains tear film and shows up epithelial damaged) cells red as in superficial punctate keratitis corneal defects. and filamentary keratitis. •• It delineates areas denuded of epithelium (abrasions, •• It is useful in diagnosis of KCS. ulcer) which stains brilliant green when examined under •• Rose Bengal dye is very irritating, so instill 2% xylocaine a cobalt blue filter. (local anesthetic) eye drop before using Rose Bengal.

Abbreviation: KCS, keratoconjunctivitis sicca. The Cornea 127

Normally, endothelial cells are hexagonal. ██ Classification Variability in the shape of cells is called Keratitis can be classified as follows: pleomorphism. In the presence of 50% nonhexa­ •• Based on depth: gonal cells, intraocular surgery is contraindicated. šš Superficial keratitis: It is the inflam­ Variation in cell size is called polymegathism. mation involving epithelium and Confocal microscopy: It is performed by a confocal Bowman’s membrane. microscope. In cases with corneal edema, endo­ šš Deep keratitis: It is the inflammation thelium is not adequately visualized by specular deep to Bowman’s membrane. microscopy due to edema. Confocal microscopy •• Based on location: may be of value in cases with corneal edema. šš Central. Confocal microscope allows direct visualization of šš Peripheral. corneal cells. It acquires multiple images of cornea •• Based on epithelial defect: from epithelium to endothelium. Magnified šš Ulcerative. images provide detailed information regarding šš Nonulcerative. cell count, shape, and size. •• Based on etiology: šš Infectious. Confocal microscopes are of two types: Confocal šš Noninfectious. slit-scanning microscope and confocal laser- scanning microscope. Infectious Keratitis (OP4.1, 4.2) ▄▄Inflammation of Cornea It is the corneal inflammation caused by bacterial, viral, fungal, or parasitic (protozoal or helminthic) Inflammation of cornea is known as Keratitis. organisms. It can be classified as: •• Depending on depth: ██ Source of Inflammation šš Superficial. Inflammation of cornea may arise from: šš Deep. •• Exogenous source: Cornea is involved by •• Depending on pus formation: way of exogenous organisms. šš Purulent (suppurative). •• Endogenous source: Inflammation due to šš Nonpurulent (Nonsuppurative). endogenous source is typically immuno­ •• Depending on epithelial defect: logical in nature. As cornea is avascular, the šš Ulcerative wherein corneal epithelium immunological changes are common near shows discontinuity. Loss of epithelium limbal blood vessels close to the corneal with inflammation in surrounding margin and called marginal keratitis. cornea is called corneal ulcer. •• Contiguous spread (owing to direct šš Nonulcerative wherein epithelium is anatomical continuity). intact (corneal abscess). •• Diseases of conjunctiva spread to corneal Inflammation in cornea is visible as a grayish epithelium, for example, trachoma and haze. If it is accompanied by accumulation of vernal keratoconjunctivitis. leucocytes and cellular debris, this hazy area is •• Diseases of sclera spread to corneal stroma, called an infiltration and appears as gray–white for example, sclerosing keratitis. or off–white opacities. Infiltrates are indicative of •• Diseases of uveal tract spread to corneal active inflammation. endothelium, for example, herpetic uveitis with endotheliitis. 128 Chapter 6

Noninfectious Keratitis •• Diphtheroids. •• Corynebacterium xerosis, etc. It is the corneal inflammation with no known infectious cause. It may be: All these organisms are nonpathogenic com­ •• Allergic/immune-mediated: mensals. Streptococci, E. coli, B proteus, Neisseria gonorrhoeae, Hemophilus aegyptius, Moraxella, 1. Localized immune-mediated keratitis: etc., are pathogenic and rarely found in normal šš Phlyctenular. eyes. šš Vernal. šš Mooren’s ulcer. Defence Mechanisms šš Marginal. The following mechanisms help in defending šš Atopic. against the microbial invasion of the corneal 2. Keratitis in systemic immunological surface: disorders: 1. Blinking regularly sweeps away debris šš Associated with collagen disorders. trapped in the mucin layer of tears. šš Dermatological disorders: Rosacea. 2. Tight junctions between corneal and – Erythema multiforme. conjunctival epithelial cells. – Mucous membrane pemphigoid. 3. Tears which contain: •• Nonimmune-mediated: •• Lactoferin (secreted by lacrimal gland): šš Neurotrophic in Vth cranial nerve (CN) It inhibits complement activation. palsy and diabetes. •• Lysozyme, which promotes microbial šš Neuroparalytic in VIIth CN palsy. aggregation and causes lysis of šš Traumatic: bacterial cell membrane. – Chemical injury. •• IgA: It causes bacterial agglutination – Thermal injury. and inhibits bacterial adherence to – Radiation. corneal and conjunctival surface. šš Mechanical: •• b-lysin: It causes bacteriolysis. – Entropion with trichiasis. 4. Mast cells of conjunctiva: Stimulation – Lagophthalmos. of mast cells cause degranulation of – Exophthalmos. mast cells. It results in vascular dilation š š Nutritional in keratomalacia. and increased vascular permeability. š š In KCS. Thus, transudate is produced which is š š Others: antimicrobial. – Thygeson’s superficial punctate 5. Resident normal microbes produces keratitis (SPK). bacteriocins (high-molecular weight pro­ – Superior limbic keratoconjunctivitis. teins), which inhibit growth of pathogens.

██ Infectious Keratitis Predisposing Factors Bacterial Keratitis Compromising one or more of the defense mecha­ nisms represent a risk factor in the development The conjunctival sac is never free from organisms. of bacterial keratitis. These mechanisms are: Most of the organisms, normally, present on the ocular surface are: Trauma: Accidental, agricultural or surgical •• Staphylococcus albus or epidermidis. (refractive surgery). •• Propionibacterium acnes. Topical steroids (cause impairment of local •• Neisseria catarrhalis. immune defense). The Cornea 129

Trigeminal nerve paralysis causes corneal However, most other bacteria are capable of anesthesia and exfoliation of epithelial cells. producing keratitis with damaged epithelium. Purulent keratitis is usually exogenous due to A—Vitamin A deficiency. pyogenic bacteria. The most common pathogens B—Bullous keratopathy (corneal epithelial are listed in Flowchart 6.2. problem). Pseudomonas aeruginosa is a frequent cause C—Chronic blepharitis. of contact lens-associated keratitis and found in Contact lens wear, particularly extended wear soft moist environments. lenses, causing hypoxia and trauma to corneal Pathogenesis of Corneal Ulcer epithelium. For a bacterial keratitis to become established, D—Diabetes mellitus. bacterial adherence to cornea requires a defect Dry eyes (Poor tear production results in reduction in the continuity of the corneal epithelium of antimicrobial tear component and epithelial (Fig. 6.7). Pathological changes occurring during desiccation and damage). development of corneal ulcer can be described

E—Entropion with trichiasis (results in breakdown of protective corneal epithelium).

F—Facial nerve palsy (results in exposure keratopathy). It does not appear that AIDS serves as an independent risk for development of infectious keratitis, but infectious keratitis in AIDS patients might follow a more aggressive course. Causative Organisms Bacteria that can penetrate normal (intact) corneal epithelium are Neisseria gonorrhoeae, Neisseria meningitidis, and Corynebacterium diphtheriae. Fig. 6.7 Bacterial corneal ulcer.

Pathogens

Gram +ve organisms Gram –ve organisms

Gram +ve cocci Gram +ve bacilli Gram –ve cocci Gram –ve bacilli • Staphylococcus aureus Aerobic: • Neisseria • Pseudomonas • Streptococcus • Bacillus cereus gonorrhoeae aeruginosa pneumoniae • Corynebacterium • Neisseria • Escherichia coli (Pneumococcus) diphtheriae meningitidis • Klebsiella Anaerobic: • Proteus • Clostridium • Moraxella

Flowchart 6.2 Types of pathogens causing keratitis. 130 Chapter 6 in four stages, namely, infiltration, ulceration, If ulcer is superficial and involves epithelium regression and cicatrization (Fig. 6.8). only, ulcer heals without leaving any opacity Stage of Infiltration behind. If ulcer involves Bowman’s membrane, some degree of permanent opacification remains, The bacterial adherence to the cornea on damaged as Bowman’s membrane never regenerates. epithelium is facilitated by binding of microbial adhesins and toxins to host cell receptors Clinical Features and glycocalyx coat. The corneal infection Clinical features depend on virulence of organism, and inflammation stimulates immigration of duration of infection, and use of steroids. polymorphonuclear leucocytes (polymorphs) via Symptoms tear film and proliferating limbal blood vessels. The epithelium becomes edematous and is raised •• Pain and photophobia (due to exposure of at the site of infiltration. nerve endings of 1st division of trigeminal [V] nerve). Stage of Ulceration •• Redness. The stage of infiltration is followed by the necrosis •• Blepharospasm. and desquamation of corneal stroma, leading •• Lacrimation. to ulceration. Polymorphs phagocytose bacteria •• Discharge. and necrotic stroma. If bacteria overwhelms •• Blurred vision. host defense, necrosis progresses unchecked and corneal perforation takes place. Signs •• Circum corneal (ciliary) congestion of Stage of Regression conjunctiva. If infection is brought under control, infiltration •• Epithelial defect is associated with gray– decreases in size. Superficial vascularization white infiltrate around the margin of ulcer. develops from the limbus which supplies Corneal lamellae imbibe fluid, and margin antibodies. Immune response increases and of ulcer becomes edematous and overhangs epithelium heals over ulcer. above the surface with sloping edges Stage of Cicatrization (saucer-shaped appearance of ulcer). Cicatrization, which occurs in vascularized ulcer, •• Corneal ulcer takes a green stain with involves regeneration of collagen and formation Fluorescein dye. of fibrous tissue. Newly formed fibers are not •• Lid erythema and edema. arranged regularly as in normal corneal lamellae. •• Anterior chamber inflammation is often These refract light irregularly. Scar is, therefore, present with cells and flare and may opaque. produce a hypopyon.

aStage of infiltration bStage of ulceration Stc age of regression dStage of cicatrization Fig. 6.8 Pathogenesis of corneal ulcer. (a) Stage of infiltration. (b) Stage of ulceration. (c) Stage of regression. (d) Stage of cicatrization. The Cornea 131

Hypopyon Corneal Ulcer individuals, debilitated persons, and Development of hypopyon: Some of the toxins alcoholics. produced by bacteria diffuse into the anterior Hypopyon corneal ulcer caused by chamber and irritate the vessels of iris and pneumococci is characteristic and is called ulcus ciliary body (keratouveitis). Polymorphs from serpens because of its tendency to creep over vessels are poured into the anterior chamber cornea in a serpiginous fashion. It starts as a and thereafter gravitate to the bottom of the gray–white or yellowish disc-like lesion near the anterior chamber to form hypopyon. Hypopyon central part of the cornea with shaggy undermined is sterile since accumulation of polymorphs is due infiltrating edges. One edge of the ulcer, along to toxins, and not to actual invasion by bacteria. which the ulcer spreads, shows more infiltration Indeed, bacteria and leucocytes are incapable of which often looks like a yellow crescent. The passing through the intact Descemet’s membrane. tissues breakdown and ulcer spreads (Fig. 6.9). Such hypopyons are fluid and always move to There is violent iritis, leading to hypopyon, the lowest part of the anterior chamber with which increases in size very rapidly. Massive change in the position of the patient’s head. Once hypopyon often causes rise in IOP (secondary the ulcerative process is controlled, hypopyon is glaucoma). easily and rapidly absorbed. In severe cases, ulcer spreads rapidly. The Thus, in absence of a full-thickness corneal entire cornea is affected by the ulcerative process perforation, hypopyon often represents a sterile and perforation of ulcer results if there is sudden accumulation. Development of hypopyon depends coughing or sneezing. on: •• Virulence of infecting organism: Pyogenic Pseudomonas corneal ulcer organisms producing hypopyon are Pseudomonas produces destructive enzymes (such as protease, lipase, elastase, and exotoxin) which melt Staphylococci, Streptococci, Gonococci corneal stroma and results in a necrotic soupy ulceration (N-gonorrhoeae), Moraxella, and with greenish-yellow mucopurulent discharge adherent to the ulcer. The corneal epithelium away Pseudomonas. from the primary ulcer typically develops a diffuse, semi-opaque The ulcer Pseudomonas and Pneumococcus (Strepto­ “ground glass” appearance. is associated with marked anterior chamber reaction coccus pneumoniae) are most dangerous and and hypopyon formation. Rapidly spreading ulcer are likely to be present if there is dacryocystitis often extends peripherally, deeply involving the entire cornea and resulting in sloughing corneal ulcer and (inflammation of lacrimal sac). perforation. If cornea sloughs, iris is prolapsed and •• Resistance of tissues: Hypopyon corneal covered by exudates which become organized, resulting ulcers are much more common in elderly in formation of pseudocornea (Fig. 6.10).

Fig. 6.9 Hypopyon corneal ulcer. Fig. 6.10 Pseudomonas corneal ulcer. 132 Chapter 6

Management of Corneal Ulcer Routes of administration could be topical, sub­ It includes identification of organism and treat­ conjunctival, or systemic. Topical administration is the route of choice because it provides rapid, high- ment. For identifying the causative organisms, levels of drugs in the cornea and anterior chamber. corneal scrapings are taken from the margins The infection is controlled by the broad-spectrum and base of ulcer for Gram’s and Giemsa staining antibiotic, while in severe infection, the fortified (Table 6.5) and culture and sensitivity (Table 6.6). antibiotic drops are preferred. Fortified drops Treatment are not commercially available and are freshly Fundamental principles for treating corneal ulcer prepared from their injectable preparations. are protection, cleanliness, and specific treatment Treatment Regimen for Topical Antibiotics of infection. Treatment should be initiated before Initial therapy should be initiated with a broad- the results of culture and antibiotic sensitivity spectrum regimen. Broad-spectrum coverage can are available. Treatment includes the use of be achieved with antibiotics and cycloplegics. •• Fluoroquinolone antibiotic alone or Antibiotics •• Combination of aminoglycoside + cephalosporin. Commonly used antibiotics are: •• Aminoglycosides, for example, Gentamicin, Since increasing resistance to fluoroquinolones Tobramycin, and Amikacin. has been reported, therapy with fluoroquinolones •• Fluoroquinolones, for example, Ciprofloxacin, is not a standard practice. Initial therapy should be Gatifloxacin, Ofloxacin, Moxifloxacin, and a combination of two fortified antibiotics: Levofloxacin. An aminoglycoside (gentamicin or tobramycin) •• Cephalosporins, for example, Cefazolin. for Gram –ve organisms •• Penicillins, for example, Penicillin G, + Methicillin, and Piperacillin. A cephalosporin (cefazolin is most commonly •• Vancomycin. used for Gram +ve organisms)

Table 6.5 Staining of corneal scrapings

Stain Organism identified

•• Gram’s and Giemsa: Gram’s staining differentiate into Gram +ve and Gram –ve species Bacteria, fungi •• Potassium hydroxide (KOH) fixation Fungi •• Calcofluor white (it is a fluorescent dye with an affinity for amoebic cysts Fungi and acanthamoeba and fungi)

Table 6.6 Corneal scrapings for culture and sensitivity

Culture media Organism isolated

•• Blood agar It promotes growth of: •• Aerobic bacteria except Neisseria, Haemophilus and Moraxella •• Saprophytic fungi •• Chocolate agar It is used to isolate neisseria, hemophilus, and moraxella •• Sabouraud’s dextrose agar Promotes growth of fungi •• E. coli plated non-nutrient agar For acanthamoeba The Cornea 133

Amikacin is useful against Gram –ve organisms prevent posterior synechiae formation as anterior resistant to gentamicin and tobramycin. The instil­ uveitis generally accompanies corneal ulceration. lation frequency of topical antibiotics is as follows: Treatment of Perforated Corneal Ulcer •• Every 1 hour day and night for 48 hours. If perforation has occurred, the treatment depends •• Every 2 hours during daytime for a further upon its size and location. Small perforation in 48 hours. pupillary area is managed with rest, anti­biotics, •• 4–6 hourly for another week. atropine, and pressure bandage. Small perfora­ Treatment is continued until epithelium has tion over iris results in adhesion of iris to cornea, healed. When combination of two antibiotics forming adherent leucoma. In case of perforation, is prescribed, drops are given in an alternating anterior chamber must be restored as quickly as fashion every half an hour. possible. It can be done by use of tissue adhesive Initial therapy with aminoglycoside and cepha­ (cyanoacrylate glue). It is applied to the area of losporin can be changed for effective treatment, perforation after careful debridement. Drying of if needed, after microbiological investigation the adhesive may take 5 to 10 minutes. A surgical (culture and sensitivity) reports. For example, procedure such as therapeutic penetra­ting fluoroquinolone treatment is significantly more keratoplasty or conjunctival flap can be under­ effective in the treatment of Neisseria infection taken thereafter. Persistent anterior stromal scar than an aminoglycoside combined with a can be removed by excimer laser phototherapeutic cephalosporin. keratectomy. Treatment Regimen for Oral Antibiotics Topical Corticosteroids in Corneal Ulcer These are not usually necessary. Systemic Steroids are best avoided, since they may retard antibiotics provide relatively low-level of anti­ epithelialization and inhibit repair by fibrosis. If biotic in the cornea because of avascularity. inflammation is severe and persists, it is safest to Therefore, these are advised only when keratitis use steroids when there is evidence of successful is complicated by scleritis (as in peripheral antibiotic treatment and cultures become sterile. ulcers with scleral extension) or there is risk of Additional therapeutic measures taken for perforation or endophthalmitis. healing of ulcer are as follows: N. gonorrhoeae should be treated systemically •• Treatment of cause š with IM ceftriaxone or IV penicillin G along with š Dacryocystitis should be treated with topical fluoroquinolone. dacryocystorhinostomy (DCR). šš If IOP is raised, it is reduced by N. meningitidis should be treated with i.v. antiglaucoma therapy. penicillin G along with topical fluoroquinolone. šš Peritomy (excision of 2 mm strip of Treatment Regimen for Subconjunctival limbal conjunctiva) is performed for Antibiotics corneal vascularization. Subconjunctival injections are indicated if there is poor compliance with topical treatment Table 6.7 Dosage of subconjunctival injections for the treatment of corneal ulcers (Table 6.7). Cycloplegics Drug Subconjunctival dose Gentamicin/tobramycin 40 mg Atropine 1% as drops or ointment is preferred. Other cycloplegics are homatropine 2% eye Amikacin 50 mg drops and cyclopentolate 1% eye drops. These are Cefazolin 125 mg instilled two to three times a day. Cycloplegics Note: Subconjunctival injections are given at 24 hourly intervals for 5 days. relieves ciliary spasm and reduces pain. These also 134 Chapter 6

•• Removal of necrotic tissue by repeated vascularization of ulcer, while systemic causes scraping of the floor of ulcer. include diabetes mellitus and systemic steroid •• Cauterization of ulcer with pure (100%) administration (Fig. 6.11). carbolic acid or 10% trichloroacetic acid. Complications •• Conjunctival flaps might be especially Following are the complications of corneal ulcers: useful in peripheral infectious ulceration. 1. Ectatic cicatrix (secondary keratectasia): If infection is brought under control, cicatri­ Deep ulcer may lead to marked thinning zation occurs in corneal ulcer. The residual scar of cornea which may bulge under normal may cause irregular astigmatism or may be IOP. The corneal scar (cicatrix) becomes visually debilitating (Table 6.8). consolidated with permanent bulging as Treatment of Nonhealing Corneal Ulcer secondary keratectasia. If ulcer does not respond to therapeutic measures 2. Secondary glaucoma: Corneal ulcer and continues to progress, a thorough search causes absorption of toxins in the anterior must be made for the cause, which could be either chamber, leading to the formation of toxic local or systemic. Local causes include lagoph­ iridocyclitis. This further causes blockage thalmos, trichiasis, raised IOP, dacryocystitis and of an angle of the anterior chamber with fibrinous exudates leading to secondary

Table 6.8 Outcome of treatment in bacterial keratitis glaucoma. 3. Descemetocele: Some ulcers become ade­ Outcome of bacterial Treatment keratitis quately deep (due to virulent organisms) to involve the whole thickness of cornea •• If irregular •• It is treated with rigid astigmatism occurs contact lens. except Descemet’s membrane. Descemet’s •• If scar is anterior •• It is removed by excimer membrane being elastic offers resistance stromal laser phototherapeutic to inflammation and is unable to support keratectomy. IOP and herniates. The herniation of •• If scar is deep •• It requires lamellar or Descemet’s membrane through the ulcer penetrating keratoplasty. is known as descemetocele. 4. Perforation of corneal ulcer (perforated Misdirected eye lashes corneal ulcer, Fig. 6.12). (trichiasis) Lagophthalmos Dacryocystitis Descemetocele is a sign of impending per­ foration which may convert into perforation on

Raised IOPVascularization of ulcer

Fig. 6.11 Local causes of nonhealing corneal ulcers. Fig. 6.12 Perforated corneal ulcer. The Cornea 135 coughing, sneezing, straining at stool, or spasm •• Iris prolapse: If perforation is large and of orbicularis muscle. Pain is alleviated after opposite the iris, iris prolapse occurs. perforation. Perforation of ulcer is accompanied by There is deposition of exudates on the iris sudden escape of aqueous and fall in IOP. The iris surface which becomes organized. Iris and lens diaphragm moves forward and cicatrization cicatricial tissue are too weak to support of corneal ulcer results (Fig. 6.13). IOP, hence anterior ectasia of cicatrix Factors responsible for preventing perforation with incarceration of iris, which is called are as follows: anterior staphyloma, develops. • •• Forced expiration (blowing the nose, • Anterior capsular cataract: If perforation coughing, etc.) must be avoided. is opposite the pupil (central perforation), •• IOP is reduced by oral acetazolamide and/ the lens comes in contact with the ulcer- or i.v. mannnitol and topical IOP-lowering causing anterior capsular cataract. If eye drops. perforation is not plugged by iris but exudates fill the gap, the repeated ruptures Sequelae and complications of perforation: The of exudates fill the gap, causing the opening effect of perforation largely depends on its size to become permanent and leading to the and position. These include the following: formation of corneal fistula. •• Endophthalmitis or panophthalmitis: Due to perforation of ulcer, organisms gain Fungal Keratitis (Mycotic Keratitis) access to the interior of the eye, leading For clinical purpose, fungi are of the following two to the development of endophthalmitis or types: panophthalmitis. •• Filamentous fungi. •• Intraocular/expulsive hemorrhage: •• Nonfilamentous fungi (yeasts). Sudden perforation of large ulcer causes sudden lowering of IOP, hence there is Risk Factors dilatation of intraocular blood vessels. This The following risk factors are involved in the leads to the development of intraocular/ development of fungal keratitis: expulsive hemorrhage (profuse bleeding •• Trauma with vegetable matter or animal along with extrusion of contents of globe). tail. •• Anterior synechiae: If perforation is small •• Systemic immunosuppression by use of and opposite the iris, anterior synechiae corticosteroids or immunosuppressives. develop, leading to leucoma adherens. •• Diabetes.

a b Fig. 6.13 (a) Perforation. (b) Descemetocele. 136 Chapter 6

•• Hydrophilic contact lens wear. Investigations helpful for coming to a diagnosis •• Corneal surgery (fungal infection at lamellar include: interface has been described following •• Scrapings from the floor of ulcer are stained LASIK). with 10% KOH. Etiology •• Scrapings are also plated on Sabouraud dextrose agar for culture and sensitivity. Fungal keratitis is rare in temperate countries but Cycloheximide should not be included in common in tropical countries, warm and humid the medium since it inhibits fungal growth. climates, rural areas, and immuno-compromised individuals. It is most prevalent in agricultural Treatment areas and typically preceded by ocular trauma As most antifungals are only fungistatic, topical with vegetable matter. It is commonly due treatment should be continued for several weeks. to infections with Aspergillus, Fusarium, and Removal of epithelium over the lesion enhances Candida albicans. penetration of antifungal agents. Clinical Features Topical treatment includes the following The onset is gradual and slowly progressive. considerations: Symptoms are relatively minimal, much milder •• Infection due to filamentous fungi is treated than clinical signs, and include foreign body with natamycin 5%, amphotericin B 0.15%, sensation, photophobia, blurred vision, and or miconazole 1% drops. Voriconazole eye discharge. drops are more effective against Aspergillus. The drops are instilled initially every 1 hour Clinical signs of filamentous fungi are: and tapered gradually. •• Organism adherence results in gray–white, •• Candida infection (yeast) is usually treated elevated infiltrate. Epithelium over infiltrate with amphotericin B. Nystatin eye ointment may be elevated above the remainder of the applied five times a day is only effective corneal surface. against candida. •• Invasion into corneal lamellae and extension along corneal lamellae results in If infection fails to respond to single agent feathery borders and satellite lesions. therapy, amphotericin B and natamycin can be •• Penetration of intact Descemet’s membrane used alternatively on an hourly basis. by filamentous fungi results in thick and Systemic antifungal drugs (itraconazole or vor­ immobile hypopyon with upper convex iconazole) may be required in endophthalmitis. border (Fig. 6.14). Infection in anterior chamber is difficult to eradicate. •• Sometimes, a white immune ring (Wessely ring) may be seen around the ulcer due to deposition of immune complexes. In case of nonfilamentous fungi (candida), keratitis is characterized by a yellow–white stromal infiltrate, associated with dense suppu­ ration, which appears as a collar-button abscess without feathery edge. Diagnosis History of trauma with vegetable matter, wood, Fig. 6.14 Fungal keratitis with satellite lesions and animal tail, or chronic use of steroid is present. hypopyon. The Cornea 137

If medical treatment fails, surgical intervention Fetus passes through the birth canal, so may be required. Penetrating keratoplasty neonatal HSV infection occurs by way of Type-2 should be performed sooner to minimize the virus (Fetus). It may affect the central nervous risk of endophthalmitis or infectious scleritis. system (CNS) or can remain localized to the Clear margins should be included in excised eye. Neonatal ocular HSV infection can present cornea. Corticosteroid use is not recommended in as conjunctivitis, keratitis, iridocyclitis, iris management of fungal keratitis. atrophy, cataract, chorioretinitis, or optic neuritis (Fig. 6.15). Viral Keratitis Primary Infection (i.e., no previous virus Viruses are obligate, intracellular parasites. exposure) Viruses that cause corneal disease include: Neonates are usually protected by maternal •• Herpes simplex virus (HSV). antibodies against HSV infection during the first •• Varicella zoster virus (VZV). 6 months of life. So, primary infection by HSV-1 •• Epstein–Barr virus (EBV). is uncommon during the first 6 months of life. •• Adenovirus. Transmission occurs by droplet transmission via •• Cytomegalovirus (CMV): It is a more contaminated adult saliva. So, children under 3 common entity in association with AIDS. years of age are more prone to get HSV infection, Herpes Simplex Keratitis owing to close contact, that is, it typically occurs HSV is a DNA virus and is of two types: HSV-1 between 6 months to 5 years of age. and HSV-2. HSV-1 causes infection above waist Primary infection remains often subclinical and and affects face, lips and eyes, while HSV-2 is may cause mild fever, malaise, upper respiratory associated with genital infection (genital herpes). tract symptoms, and local lymphadenopathy. Oral HSV infection can be categorized into neonatal, mucosa is more commonly involved than eye in primary, and recurrent infections. primary infection.

Neonatal Infection Children may develop follicular kerato It is the infection of newborns by maternal genital conjunctivitis. Epithelial punctate keratitis herpes. may be found in nearly 50% of the cases. Primary

Fig. 6.15 Presentation of neo­ natal ocular HSV. Abbreviation: 1. Conjunctivitis HSV, herpes simplex virus.

2. Keratitis

3. Iridocyclitis and iris atrophy

6. Optic neuritis

4. Cataract 5. Chorioretinitis 138 Chapter 6 herpetic infection is usually benign and self-limited. Virus replication results in opaque epi­ An attack does not produce lasting immunity and thelial cells on the cornea, arranged in a recurrences are frequent, particularly associated row or group. Central desquamation of with upper respiratory tract infection (URTI). A these results in linear branching ulcer person once infected frequently becomes a carrier. (dendritic ulcer). The ends of the ulcer have characteristic terminal knobs which Recurrent Infection (i.e., reactivation in presence of cellular and humoral immunity) are pathognomonic. The central ulcerated area stains with Fluorescein dye, while the After primary infection with HSV-1, the virus peripheral cells at the margin containing reaches the sensory ganglion, where it may lie live virus stain with Rose Bengal dye. dormant for many years. Risk factors for recur­ Indiscriminate use of topical steroids results rence are fever, stress, trauma, malnourishment, in progressive enlargement of dendritic measles, and use of corticosteroids and other ulcer to an amoeboid or geographical con­ immunosuppressive. figuration known as geographical ulcer. The above stimuli (risk factors) may cause a •• Corneal sensation is reduced. The ulcer may clinical reactivation and replication of the virus. resolve spontaneously or with treatment The virus travels down the sensory ganglion (e.g., over 1 to 2 weeks. A nonhealing epithelial trigeminal ganglion) and result in recurrent ocular defect after live virus disappears with HSV disease. Fortunately, ocular HSV disease prolonged topical treatment is referred to tends to be a form of unilateral disease. as “metaherpetic” ulcer. It is caused by basement member damage, resulting in Clinical Features failure of reepithelialization. It is not caused Clinical features depend upon the part affected. by reactivation of virus (viral replication). Recurrent ocular HSV infection can affect lids, Margins of these ulcers do not stain with Rose conjunctiva and cornea (epithelium, stroma and Bengal. endothelium). IV. Involvement of corneal stroma: Stromal lesion Note: Epithelial lesions are caused by might be an immunological reaction, be infectious, replicating live virus. Stromal and endothelial or may involve combined mechanism. Stromal lesions involve both live virus activity and lesions in herpetic disease include disciform immune reaction to viral antigen.

I. Involvement of lids causes lid vesicles and blepharitis.

II. Involvement of conjunctiva manifests as severe follicular conjunctivitis.

III. Involvement of corneal epithelium by way of HSV results in epithelial keratitis. Symptoms include mild discomfort, foreign body sensation, redness, watering, blurred vision, and photophobia.

Following are the clinical signs of involvement of corneal epithelium due to recurrent HSV infection: Fig. 6.16 Dendritic ulcer. Source: Uveitis. In: Glass L, •• Characteristic epithelial lesion of recurrent ed. Ophthalmology Q&A Board Review. 1st Edition. HSV infection is dendritic ulcer (Fig. 6.16). Thieme; 2019. The Cornea 139

Immunological reaction Low-grade endotheliitis between viral antigens and host antibodies

Mild anterior uveitis Aqueous into stroma Deposited in stroma as Wessely ring

KP’s Disc-shaped stromal Oedema

Corneal thickening and folds in Descemet’s membrane

Flowchart 6.3 Signs of disciform keratitis.

keratitis and stromal necrotizing keratitis. Typical lesion has a cheesy, yellow–white Disciform keratitis: It is a hypersensitivity reaction necrotic appearance. There may be associated to HSV antigen in the cornea. Symptoms include anterior uveitis with KPs. Scarring, vasculariza­ blurred vision and halos around lights. Following tion, and lipid deposition are common. are the clinical signs of disciform keratitis due to •• In advanced disease, corneal stromal recurrent HSV infection (Flowchart 6.3): melting results in descematocele formation •• Disc-shaped stromal edema, often with and perforation. overlying epithelial edema, is a dominant •• If peripheral cornea is involved, inflam­ feature. mation and necrosis spread to sclera, •• Folds in Descemet’s membrane. resulting in sclerokeratitis. •• Mild anterior uveitis with keratic preci­ V. Involvement of corneal endothelium pitates (KPs). (endotheliitis) results in corneal edema, anterior •• A ring of stromal haze may be present uveitis, which in turn leads to hypopyon and surrounding the stromal edema called the synechiae formation, and trabeculitis resulting in Wessely ring. It signifies deposition of viral elevated IOP. antigen and host antibody complexes. •• Corneal sensations are reduced. There is no Complications stromal neovascularization or necrosis. Complications of herpetic eye disease include: Stromal necrotizing keratitis: It is caused •• Secondary infection. by active viral invasion. The infiltration of cornea •• Secondary glaucoma. by polymorphs, lymphocytes, macrophages, •• Cataract (secondary to inflammation or and plasma cells mediate tissue destruction and prolonged use of steroids). stromal necrosis. •• Iris atrophy (secondary to keratouveitis). 140 Chapter 6

Diagnosis šš Vidarabine (Ara - A) 3% ointment Diagnosis of ocular HSV disease is based on a 5 times daily. constellation of: TFT and acyclovir both are active against HSV-1 •• Assessment of corneal sensations. and HSV-2. •• Staining characteristics with Fluorescein Early IDU (Idoxuridine) 0.1% drops and 0.5% and Rose Bengal dye. ointment were used, but due to the relative toxic •• Enzyme-linked immunosorbent assay effect on epithelium (punctate keratopathy), it is (ELISA) test identifying viral antigens. seldom used now. The most frequently used drug •• Polymerase chain reaction (PCR) which is Acyclovir 3% ointment. Recently, Ganciclovir detects HSV viral DNA in tissues, aqueous, 0.15% gel 5 times daily is effectively used. and tears. Antiviral agents are used until the epithelial ulcer Treatment has healed. Treatment of HSV ocular disease depends on the 3. Lubricants are also given. nature of ocular involvement. Ocular HSV disease 4. Cycloplegics, if required. is treated by antiviral agents. These are purine or 5. Topical antibiotics to prevent secondary pyrimidine analogues that are incorporated to bacterial infections. form abnormal viral DNA. 6. Topical steroids are contraindicated in epithelial HSV keratitis because of the To define the role of oral antiviral agents and topical presence of active viral replication in corticosteroids in the treatment and prevention of recurrent HSV ocular disease, a study termed Herpetic HSV epithelial keratitis. Eye Disease Study (HEDS) was conducted. According to HEDS: Advantages of acyclovir over IDU, TFT, and Vidarabine. 1. Oral acyclovir: Provides no extra benefit over topical 1. It has less epithelial toxicity. steroids and topical antiviral agents in treatment 2. It penetrates intact corneal epithelium and stroma, of stromal keratitis. It provides benefit in HSV achieving therapeutic levels in aqueous humour. iridocyclitis. So, concurrent administration of oral 3. It acts preferentially on virus-laden epithelial cells acyclovir is recommended in HSV iridocyclitis. It and has low-toxicity for host cells. does not seem to prevent recurrent stromal keratitis or iridocyclitis. •• Treatment of metaherpetic ulcers 2. Topical steroids: In absence of accompanying HSV (postinfectious ulcer): If ulcer is truly epithelial keratitis, topical steroids along with topical antiviral agents reduce progression of stromal metaherpetic, that is, persistent epithelial inflammation and shorten the duration of stromal defect after live virus disappears with keratitis (i.e., stromal keratitis improves more rapidly). topical treatment; antiviral agent serves no purpose and most likely will only •• Treatment of epithelial keratitis without inhibit epithelial regeneration. Treatment stromal involvement includes the following is directed toward encouraging epithelial considerations: healing and includes: 1. Debridement of the edges of dendritic šš Lubrication of eye with preservative free ulcer with cotton-tipped applicator to drops. reduce infected (virus-laden) epithelial šš Therapeutic (bandage) soft contact lens. cells. šš Temporary tarsorrhaphy (if above 2. Antiviral agents: measures fail) (OP4.7). šš TFT (Trifluorothymidine) 1% drops šš Conjunctival flap. every 2 hours •• Treatment of stromal keratitis: It is treated or with topical steroids and topical antiviral The Cornea 141

agents. Important points of consideration Varicella-Zoster Virus Keratitis (VZV Keratitis) are: Varicella-zoster virus causes varicella (chicken­ š š Topical Prednisolone (1% drops) is used pox) on initial infection and zoster or shingles on 4 to 5 times daily and gradually tapered. recurrence (herpes zoster). Thus, herpes zoster It reduces inflammation. is caused by same virus that causes chicken pox. š š Acyclovir 3% ointment is recommended After initial varicella (chicken pox) infection in five times daily. It penetrates intact childhood or youth, the virus remains latent in corneal epithelium and stroma and a sensory ganglion (like herpes simplex virus). It can therefore be used to treat stromal can reactivate to cause shingles (herpes zoster) herpetic keratitis. after depressed cellular immunity. Depressed Oral acyclovir provides no extra benefit over cellular immunity can occur with age, AIDS, immu­ topical steroids and topical antiviral agents in nosuppressives, blood dyscrasias, neoplasms, and treatment of stromal keratitis. radiotherapy. Thus, herpes zoster represents a •• Treatment of patients with HSV irido­ form of recurrent disease. cyclitis: HSV endotheliitis, trabeculitis, The virus travels via sensory nerve to skin and iridocyclitis are treated with topical dermatome or eye where peripheral inflammation steroids (Prednisolone 1% drops tapered develops. Trigeminal nerve infection is second gradually) plus topical antiviral agent in frequency as a site of recurrence after the (Acyclovir 3% ointment five times daily) thoracic region. and oral Acyclovir (400 mg five times daily Herpes zoster ophthalmicus (HZO) is a for 7–10 days). consequence of Gasserian ganglion (trigeminal •• To reduce rate of recurrent herpetic eye nerve) involvement. Involvement of ophthalmic disease: Low-dose oral Acyclovir 400 mg (1st) division occurs far more commonly than BD for 6 to 12 months reduces the rate of involvement of 2nd or 3rd divisions of trigeminal recurrent HSV ocular disease but this effect nerve. Of the 1st division, frontal nerve is the most reduces or even disappears when the drug commonly involved branch. The virus travels via is discontinued. So, long-term prophylactic branches of ophthalmic division of trigeminal treatment should be considered in patients nerve to the skin, eye, and adenexae (Fig. 6.17). with frequent recurrences and at the risk of visual loss, particularly involving an only eye. •• Patients with stromal scarring and opacity can be treated by penetrating keratoplasty (PKP). Recurrence of active herpetic infection in corneal grafts is often a problem. Since long-term oral antiviral treatment can reduce recurrence rate, oral Acyclovir 400 mg BD should be given to patients undergoing PKP for herpetic eye disease to improve the survival of corneal Fig. 6.17 Herpes zoster ophthalmicus. Source: The grafts. diagnosis of binocular diplopia. In: Biousse V, Newman N, ed. Neuro-ophthalmology illustrated. 3rd Edition. Thieme; 2019. 142 Chapter 6

Pathology The skin of lid and affected area becomes There is prominent vasculitis with granulomatous red and edematous. The vesicles suppurate or lymphocytic infiltration. Tissue damage caused before they crust and leave behind pitted scars. by zoster infection is due to both inflammation Anesthesia of skin follows as the eruptions and vasculitis-induced ischemia. subside. Clinical Features Postherpetic neuralgia is the pain that persists for months to years after the skin lesions Prodromal stage of HZO precedes the appearance (rashes) have healed. of rashes (eruptive stage) and lasts 3 to 5 days. The disease starts with fever, malaise, and headache Contact with nonimmune or immunosuppressed followed by neuralgic pain along the distribution individuals should be avoided until the crusting is of the 1st division of the trigeminal nerve. complete. Eruptive stage follows the prodromal stage Ocular involvement: Ocular complications and lasts for approximately 3 weeks. The vesicles arise as the eruptions subside. The eye is appear on one side of the forehead of the scalp frequently affected if the vesicles appear on the along the distribution of the ophthalmic division tip and the side of the nose due to involvement of the trigeminal nerve and does not cross the of the nasociliary branch of the trigeminal nerve midline. The pain sometimes diminishes after the (Hutchinson sign). The eye involvement may appearance of vesicles but may persist for months rarely occur when disease affects maxillary nerve or years. (2nd division of trigeminal nerve) (Table 6.9).

Table 6.9 Ocular manifestations in HZO

Structure involved Ocular manifestation

•• Involvement of lid •• Lid scarring may result in cicatricial entropion or ptosis. •• Involvement of conjunctiva •• Conjunctivitis is common. It can be follicular or necrotizing. •• Involvement of sclera •• Scleritis may become chronic and frequently recurrent, leading to staphyloma. •• Involvement of cornea •• Corneal involvement in acute phase can manifest as: šš Punctate epithelial keratitis. šš Dendritic lesions (in contrast to HSV dendrites, these have tapered ends without terminal bulbs). šš Nummular keratitis. šš Disciform keratitis. šš Sclerokeratitis. šš Kerato uveitis. •• Chronic corneal lesions that follow HZO are: šš Mucous plaque keratitis. šš Neurotrophic keratitis. šš Exposure keratitis. •• Involvement of uvea •• Anterior uveitis is frequently associated with sector iris atrophy. •• Involvement of trabecular •• Trabeculitis may cause secondary glaucoma. meshwork •• Occlusive vasculitis •• It may cause ARN and anterior segment ischemia. •• Involvement of optic nerves •• Optic neuritis is rare and a late complication. •• Involvement of motor nerves •• HZO affecting 3rd, 4th, and 6th CN results in extraocular muscle palsy, while facial N (7th CN) involvement results in facial palsy (Bell’s palsy). Abbreviations: ARN, acute retinal necrosis; CN, cranial nerve; HSV, herpes simplex virus; HZO, herpes zoster ophthalmicus. The Cornea 143

Treatment •• Topical steroids and antiviral eye ointment A. Treatment of acute systemic herpes zoster. are given if there is scleritis, sclerokeratitis, or iridocyclitis to reduce inflammation. 1. Systemic antiviral agents: Oral Acyclovir – Steroids are tapered gradually. 800 mg five times daily × 7 to 10 days and •• Major complication of HZO, neurotrophic initiated within 72 hours of the onset of ulceration, is treated with bandage con­ symptoms. tact lens, tarsorrhaphy (OP4.7), and cyano­ It accelerates healing of skin lesions. It reduces acrylate glue/penetrating keratoplasty (in period of viral shedding, severity of acute pain, case of corneal perforation). incidence of episcleritis, keratitis, and iritis. Other antivirals are oral Famciclovir 500 mg TDS × 7 Parasitic Keratitis to10 days and oral Valaciclovir 1000 mg TDS × 7 Acanthamoeba Keratitis to 10 days. It is caused by Acanthamoeba (a protozoan) found 2. Systemic steroids are used in combination in soil and water environments such as ponds, with antiviral agents. These are not only swimming pools, contact lens solutions, and tap recommended to reduce acute pain but water. also used in the treatment of inflammatory complications of HZO such as severe Source of infection scleritis, uveitis or orbital inflammation. •• Contact lens solutions are the usual Dose: 60 mg/day and then reduced source of infection. Once contact lens gradually. is contaminated, risk of infection is

B. Treatment of postherpetic neuralgia. established, since the organism can adhere to and penetrate an intact epithelium. Nonsteroidal anti-inflammatory drugs (NSAIDS) •• Swimming or bathing in contaminated are ineffective in postherpetic neuralgia. Initially, water may be the source in noncontact lens it is treated with: wearers. Topical Lidocaine 5% gel (local anesthetic) or Acanthamoeba exists in dormant cystic topical Capsaicin cream (depletes substance P). form and active trophozoite form. Trophozoite If it is ineffective, then the following drugs are produces a variety of enzymes and binds to given: corneal epithelium, resulting in thinning and •• Amitriptyline (a tricyclic antidepressant)— necrosis of corneal epithelium. Early infection can 12.5 to 25 mg at night and increased be confined to the epithelium, but in advanced gradually to 75 mg/day, or cases, the organism can enter the stroma and •• Carbamazepine 400 mg daily to reduce anterior chamber. pain. Clinical Features C. Local ocular treatment of HZO. Symptoms of acanthamoeba keratitis include For cutaneous lesions, antibiotic–corticosteroid severe ocular pain, blurred vision, photophobia, skin ointment is applied on skin and lids. and lacrimation. Calamine lotion is better avoided as it promotes crust formation. In the eye itself: Clinical signs of acanthamoeba keratitis •• Topical antivirals are not effective. include the following: •• Topical antibiotics are instilled to prevent •• Early infection is confined to the epithelium secondary bacterial infection in acute stage which shows irregular surface as well as of disease. infiltrates and pseudodendrites mimicking 144 Chapter 6

H simplex keratitis. The epithelium is intact •• Azoles (destabilize cell walls) include initially and later breaks down. Clotrimazole, Fluconazole, Ketoconazole, •• Deep linear stromal infiltrates might and Miconazole. be seen around corneal nerves (radial •• Aminoglycosides (disrupt plasmalemma keratoneuritis) and are pathognomonic. of organism) include Neomycin and •• The infiltrates coalesce to form a ring Paromomycin. abscess in stroma and resemble stromal •• Aromatic diamidines (inhibit DNA herpetic disease. Scleritis may develop. synthesis) include Propamidine isethionate, In spite of severe inflammation, corneal Hexamidine, and Pentamidine. vascularization is typically absent. Topical ameobicides are given as dual therapy •• Corneal melting may occur at the periphery (diamidines + cationic antiseptics) with: of the area of infiltrates. Satellite lesions can •• Propamidine isethionate + PHMB drops appear. Anterior chamber inflammation can cause anterior uveitis and hypopyon. or Differential Diagnosis Hexamidine + Chlorhexidine This condition should be differentiated from Topical neomycin and miconazole are quite herpetic keratitis and fungal keratitis. Patients effective. The diseases may require a prolonged with acanthamoeba keratitis are younger treatment for several months. Since cysts are than patients with bacterial keratitis or fungal difficult to eradicate, stromal relapses are keratitis, and have a longer duration of symptoms common, as treatment is tapered. before being treated. In terms of clinical signs, •• Topical steroids should be avoided, if acanthamoeba keratitis is more likely to have possible. disease confined to the epithelium and ring •• Persistent corneal inflammation occurs infiltrate. due to necrotic protozoa (acanthamoeba antigen) rather than viable organism and Diagnosis may result in scarring and impaired vision. •• Staining of corneal scrapings with calcofluor PKP is needed for residual scarring. white stain. It is a fluorescent dye with an affinity for amoebic cysts which ██ Noninfectious Keratitis demonstrates the walls of the cysts but requires a fluorescent microscope. Interstitial Keratitis (IK) •• Polymerase chain reaction (PCR) to detect It is an inflammation of the corneal stroma acanthamoebic DNA. without primary involvement of epithelium or

Nonsuppurative keratitis in a contact lens endothelium. wearer is a high-index of suspicion, and treatment Etiology should be as for acanthamoeba infection. It is most often associated with congenital Treatment syphilis but may also be seen in acquired syphilis, tuberculosis, leprosy, and viral infections It includes the following considerations: ( ). (IK and deafness) Debridement to remove infected epithelium for Table 6.10 Cogan’s syndrome is a rare cause affecting both eye and ear. early disease. Topical antiamoebics which include: •• Cationic antiseptics (inhibit membrane IK due to congenital syphilis occurs via function) include Chlorhexidine and PHMB transplacental route, usually bilateral, and affects (polyhexamethylene biguanide). children between the ages of 5 and 25 years. The Cornea 145

In IK, the uveal tract is almost always affected. Clinical Features The disease is fundamentally uveitis and keratitis Symptoms include pain, blurring of vision, is secondary. Keratitis is the result of immune- photophobia, and watering of eyes. mediated reaction. Treponema pallidum is not Following are the clinical signs of IK: seen in cornea even during the acute phase. •• Signs in progressive stage: Keratic preci­ Course of the Disease pitates, ciliary congestion, and ground glass It is divided into three stages: Progressive, florid, appearance of cornea with stromal edema. and regressive stages. •• Sign in florid stage: Deep vascularization with salmon patch. Progressive Stage •• Sign in regressive stage: Ghost vessels. Since The cellular infiltration in deeper layers of cornea infiltration of cornea is almost limited to (just anterior to Descemet’s membrane) occurs deeper layers, ulceration of corneal surface after anterior uveitis with ciliary congestion. is rare. The stromal cloudiness involves the whole Diagnosis cornea, giving it a ground glass appearance in 2 It depends on: to 4 weeks. Anterior uveitis may be obscured by •• Other evidences of congenital syphilis corneal clouding. include: Florid Stage šš Frontal eminence. In this stage, deep vascularization of stroma šš Flat nasal bridge. occurs. The vascular growth begins at the limbus šš Hutchinson’s teeth (notching of two and grows in a brush-like manner. Since these upper central incisors in permanent vessels are covered by hazy cornea, vessels look dentition). dull reddish pink, resulting in a characteristic šš Vestibular deafness. salmon patch. There is superficial vascularization šš Rhagades at the angles of the mouth. but it never extends far over the cornea. •• Hutchinson’s triad includes IK, Conjunctiva may heap up at the limbus. Hutchinson’s teeth, and vestibular deafness. Coagan’s syndrome include non syphillitic Regressive Stage IK and deafness. In this stage, stromal vessel become nonperfused •• Serological tests: All patients with IK and remain as fine opaque lines (empty or ghost should have treponemal serology including vessels), which indicates the previous occurrence rapid reagin test, FTA–ABS (fluorescent of the disease. The cornea clears slowly from treponemal antibody absorption) test, periphery toward center. If cornea does not clear and venereal disease research laboratory within 18 months, visual prognosis is poor. (VDRL) test.

Table 6.10 Differentiating features of syphilitic and tubercular IK

Syphilitic IK Tubercular IK

Laterality Usually bilateral Usually unilateral Involvement Involves whole cornea Frequently sectorial involving lower sector of cornea Treatment (Systemic) Antisyphilitic Antitubercular (Topical treatment is same in both)

Abbreviation: IK, interstitial keratitis. 146 Chapter 6

Treatment •• A limbal phlycten may extend onto the Active IK is dealt with the help of: cornea and appear as slightly raised above the corneal surface. The overlying •• Systemic treatment with penicillin and epithelium breaks down and a triangular systemic steroids tapered gradually. yellowish ulcer is formed with prominent •• Topical treatment with topical steroids vascularization known as fascicular ulcer. (as IK is a hypersensitivity reaction), and cycloplegics for uveitis. As the disease is essentially conjunctival, so •• Lubricating eye drops. the epithelium and superficial layer of cornea •• PKP in cases with dense corneal opacity. are involved. The ulcer remains superficial and seldom perforates. A healed corneal phlycten Immunologically Mediated Keratitis leaves a triangular scar associated with superficial Immunologically mediated keratitis includes the vascularization and thinning. following: Treatment •• Keratitis secondary to conjunctival diseases, Treatment includes use of topical steroids, topical for example, phlyctenular keratitis and antibiotics, and cycloplegics, in case of corneal vernal keratitis. involvement. •• Marginal ulcer (catarrhal ulcer). •• Mooren’s ulcer. It is also essential to treat associated staphy­ •• Keratitis associated with collagen vascular lococcal blepharitis. disorders such as rheumatoid arthritis, Vernal Keratitis systemic lupus erythematosus (SLE), Cornea can be involved in up to 50% of cases with polyart­eritis nodosa, and Wegener’s vernal keratoconjunctivitis. It is more frequent in granulomatosis. palpebral type of disease. Several types of corneal Phlyctenular Keratitis lesions may be produced such as: •• Punctate epithelial keratitis which begins Cornea is often involved in phlyctenular kerato­ as discrete micro erosions in the superior conjunctivitis, which is essentially a conjunctival cornea (punctate epithelial erosions). disease. •• Epithelial macro erosion due to continued Phlyctens are commonly found at the limbus epithelial loss. but may occur within the corneal margin (corneal •• Shield ulcer (vernal ulcer): A vernal ulcer phlycten). is noninfectious, horizontally oval, shallow, Etiology nonvascularized, and indolent ulcer of the superior cornea. It is associated with sub­ It is thought to be delayed hypersensitivity epithelial scarring and mild corneal opacity. (Type IV and cell-mediated) to an endogenous Chronic inflammation in the absence of microbial antigen, mostly staphylococcal or ulcer may develop peripheral superficial tubercular. vascularization, especially superior. Clinical Features Treatment Symptoms include photophobia, lacrimation, •• Punctate epithelial keratitis responds blepharospasm, and pain. Corneal phlyctens cause to usual treatment of vernal kerato- much pain and photophobia. conjunctivitis. Clinical signs of phlyctenular keratitis include: •• For persistent epithelial defects with •• Phlycten appears as a gray nodule at the ulceration, amniotic membrane graft with limbus, which is associated with superficial lamellar keratoplasty is carried out to vascularization. enhance reepithelialization. The Cornea 147

Marginal Ulcer (Catarrhal Ulcer) It may be unilateral or bilateral and affects Marginal ulcer is a superficial ulcer situated near males more commonly than females. Unilateral the limbus and frequently seen in old people. involvement affects older patients, is slowly progressive and responds better to treatment; Etiology bilateral involvement affects younger patients It is thought to be caused by immune reaction and is more aggressive. to exotoxins produced by Staphylococcus aureus. Clinical Features These ulcers may also be caused by Moraxella and Haemophilus. They are often associated with Symptoms include severe pain, lacrimation, Staphylococcal blepharitis in which an immune photophobia, and blurred vision due to irregular reaction occurs in the toxins produced by astigmatism. staphylococcus. This antigen–antibody complex is It begins as gray infiltrates near the margin of deposited in the peripheral cornea with secondary the cornea which breakdown, forming peripheral lymphocytic infiltration. ulcer. The ulcer spreads circumferentially and Clinical Features toward the center of the cornea. Typically, advancing edge of ulcer undermines the corneal Symptoms include mild irritation, lacrimation, epithelium and superficial stroma. The base of photophobia, and pain. The subepithelial marginal the ulcer soon becomes vascularized. Healing infiltrates, separated from limbus by a clear zone takes place behind the active margin of the ulcer, of cornea, are typically located at the point of but the healed area remains thin, vascularized contact of eyelids with cornea (i.e., at 4, 7, 10, and and opaque. It rarely perforates. Spontaneous 2 o’clock positions). The infiltrates coalesce with perforation is rare; however, minor trauma may the circumferential spread which is accompanied lead to perforation. by the breakdown of overlying epithelium. The ulcer formed is shallow and frequently become Differential Diagnosis vascularized. Resolution occurs but recurrences are It includes the conditions that are characterized common and ulcer runs a chronic indolent course by peripheral corneal ulceration and/or melting. (Fig. 6.18, Table 6.11). Differentiating features Patients with bilateral Mooren’s ulcer must be between marginal keratitis and bacterial keratitis investigated for collagen vascular disorders. can be remembered by the mnemonic, PEDAL. Treatment Lesions are culture negative, but S. aureus can Treatment for Mooren’s ulcer is difficult and frequently be isolated from lid margins. disappointing as ischemia is the underlying cause. Treatment Stepladder approach to manage this aggressive Treatment includes topical antibiotic + steroid disease includes local, systemic, and surgical drops. Treatment of coexisting blepharitis is done therapy. to prevent recurrences. •• Local treatment includes: Topical treat­ Mooren’s Ulcer ment with corticosteroids, cyclosporine, and Acetylcysteine 10% (collagenase It is a rare peripheral ulcerative keratitis also inhibitor). Conjunctival resection is done if known as chronic serpiginous ulcer or rodent inflammation is not controlled. It eliminates ulcer. conjunctival sources of collagenase, Etiology proteo­glycanase, and other inflammatory Its exact etiology is unknown but autoimmune mediators. mechanism appears to be involved. It can be •• Systemic treatment: Systemic immuno­ triggered in genetically susceptible individuals by suppression with cyclophosphamide, cyclo­ trauma. sporine, steroids, or methotrexate may be 148 Chapter 6

Table 6.11 Comparison between marginal and bacterial keratitis (i.e., distinction between noninfectious and suppurative infiltrates)

Marginal keratitis Bacterial keratitis

Pain Less More Epithelial defect Small or absent (<1 mm) Present (>1 mm) Discharge Watery Purulent Anterior chamber reaction (uveitis) − + Location Peripheral Central

██ Miscellaneous Keratitis

Superficial Keratitis It involves corneal epithelium, Bowman’s membrane, and superficial corneal stroma. It is divided into: •• Superficial punctate keratitis (SPK). •• Superior limbic keratoconjunctivitis. •• Filamentary keratitis. •• Recurrent corneal erosions. •• Photophthalmia.

Fig. 6.18 Peripheral ulcerative keratitis (PUK). Superficial Punctate Keratitis (SPK) It is characterized by multiple, punctate lesions in initiated if the treatment with conjunctival the superficial layers of the cornea (Fig. 6.19). It is resection fails. caused by: •• Surgical treatment: It includes lamellar •• Viral infections: Most common causes are: keratoplasty and cyanoacrylate glue to adenovirus, H-simplex, and H-zoster. treat small perforations. •• Chlamydial infections: Trachoma and inclusion conjunctivitis. Lamellar keratoplasty with systemic immunosuppression •• Toxic: It may be due to staphylococcal may reduce the risk of recurrence; without systemic immunosuppression, recurrence rate is high. toxins in blepharoconjunctivitis. •• Dry eye syndrome: In KCS. •• Idiopathic: Thygeson’s SPK. Conditions causing peripheral corneal ulceration and thinning: Location •• Marginal ulcer. •• Mooren’s ulcer. Location of lesions may serve as a clue to the •• Systemic collagen vascular disorders: etiology of SPK. šš Rheumatoid arthritis. šš Polyarteritis nodosa. Superior location of SPK: The probable etiology šš SLE. may be vernal keratoconjunctivitis (VKC), superior šš Wegener’s granulomatosis. •• Oculo-dermatologic conditions: limbic keratoconjunctivitis (SLK), and trachoma. šš Rosacea keratitis. •• Corneal degenerations: Inferior location: The probable etiology is šš Terrien’s marginal degeneration. Staphylococcal blepharitis, trichiasis, entropion, šš Pellucid marginal degeneration. and lagophthalmos. The Cornea 149

chronic course with remissions and exacerbations. Thyroid function tests should be performed due to strong association with thyroid disease. Clinical Features Symptoms include foreign body sensation, burning, irritation, redness, watering, and photophobia. Characteristic signs are seen in cornea and conjunctiva: •• Conjunctiva: Hyperemia of superior bulbar conjunctiva and opposing superior tarsal (palpebral) conjunctiva with papillary Fig. 6.19 Superficial punctate keratitis. reaction is marked. •• Cornea shows filamentary keratitis of the superior cornea and limbus. Interpalpebral location: The probable etiology šš SPK in the superior part of cornea which is seborrheic blepharitis and KCS. stains with Fluorescein and Rose Bengal. Clinical Features šš Superior corneal pannus. Symptoms include mild ocular discomfort, •• KCS in 25 to 50% of cases. photophobia, and lacrimation. It is characterized Treatment by punctate epithelial lesions which stain with Treatment is symptomatic as the condition is Fluorescein dye. Subepithelial lesion may be usually self-limiting and include the following: present which do not stain with Fluorescein dye. •• Topical lubricants to reduce friction It is usually associated with conjunctivitis. between lid and bulbar conjunctiva. One of the most characteristic features of Lubricant must be preservative-free. Thygeson’s SPK is lack of associated conjunctival •• Topical steroids to reduce inflammation. inflammation (conjunctivitis). All other disease •• Topical Acetyl Cysteine drops (10%) for entities have associated conjunctivitis. filamentary keratitis. Treatment •• Topical retinoic acid to prevent keratinization. It is treated with topical steroids with gradual •• Punctal occlusion as 25 to 50% patients with tapering, lubricants, and treatment of cause. SLK also have KCS (dry eyes). Superior Limbic Keratoconjunctivitis (SLK) •• Soft contact lenses which intervene As the name suggests, it is superior, limbic, corneal between lid and superior bulbar conjunctiva and conjunctival inflammation. It typically affects and may be useful. those belonging to the middle age group, with •• Resection of superior limbal conjunctiva a greater affinity for females than males. It is and Tenon’s capsule. usually bilateral. It is associated with abnormal Filamentary Keratitis thyroid dysfunction, usually hyperthyroidism. It is a superficial keratitis associated with Its exact etiology is unknown. It appears to be formation of corneal filaments. the result of blink-related mechanical trauma which is supported by increased lid apposition of Etiology exophthalmic thyroid patients, who are known KCS is the most common cause. Other causes to have an increased incidence of SLK. SLK runs a include recurrent corneal erosions, H. simplex 150 Chapter 6 keratitis, prolonged eye patching, neurotropic Characteristic Signs of recurrent corneal keratitis, and SLK. erosions include the following: • Clinical Features • Frank epithelial defects, particularly in the lower part of cornea. Symptoms include irritation and foreign body •• Signs of epithelial basement membrane sensation. Filaments consist of the core of mucous dystrophy (intraepithelial microcysts and strands lined with epithelium. One end of the finger print lines) may be present in both filament is attached to the corneal epithelium, eyes. while the other is unattached (free), moves with each blink, and causes foreign body sensation. Typically, onset of corneal erosion occurs upon awakening in the morning, although it may occur They stain well with Rose Bengal (Fig. 6.20). at any time. Sleep causes relative anoxia, leading Treatment to edema of corneal epithelium. Vulnerable Treatment includes the following: epithelium is easily rubbed off on sudden opening •• Mechanical removal of filaments. of eyelids upon awakening. •• Hypertonic 5% saline drops to encourage Treatment adhesion of loose epithelium. •• A topical mucolytic agent such as Acetyl Treatment includes the following: • Cysteine (10%). • Lubricants: Eye drops during waking hours •• Bandage contact lens. and gel or ointment at night. • •• Treatment of underlying cause. • Therapeutic soft contact lenses (bandage •• Short-term topical steroids. contact lens). •• Topical antibiotics and cycloplegics. Recurrent Corneal Erosions •• If erosions are severe or frequent, excimer It is characterized by recurrent breakdown of laser phototherapeutic keratectomy can be epithelium. The basic cause is abnormalities in the performed. underlying basement membrane microstructure. •• Anterior stromal micropunctures over and The condition may be associated with trauma, surrounding the erosions not involving the epithelial basement membrane or anterior visual axis. stromal dystrophy, and diabetes. Photophthalmia Pathogenesis It is caused by exposure to ultraviolet (UV) rays in Trauma or epithelial basement membrane the range of 290 to 311 nm. UV damage to cornea dystrophy results in microscopic derangement is both wavelength- and intensity-dependent. in the epithelial basement membrane (such as thickening and discontinuity). It leads to abnormally weak attachment between basal cells of epithelium and basement membrane. Thus, epithelial layers are prone to separation and frequent erosions. Minor injuries such as opening the eyes after sleep can cause shearing forces, resulting in tearing of epithelium. Clinical Features Symptoms often occur on wakening and include severe pain, blurring, photophobia, foreign body sensation, blepharospasm, and watering. Fig. 6.20 Filamentary keratitis. The Cornea 151

For short wavelength, a very small amount of 3. Systemic diseases such as diabetes UV energy may produce a corneal lesion. Nucleic (peripheral neuropathy may result in acids of corneal epithelium maximally absorb decreased corneal sensation) and leprosy. these wavelengths. Sources of UV rays are welding Pathogenesis of neurotrophic keratitis is flashes, germicidal lamps, and snow surface. explained in Flowchart 6.4.

Most damaging range of wavelength is 260 to 290 nm Clinical Features but absorbed by ozone layer. So, radiation of these Symptoms include red eye, absence of pain, wavelengths rarely penetrates the Earth’s surface. decreased aqueous tear production, mild foreign Pathology body sensation, and blurred vision. After 4 to 6 hours of exposure to UV rays damaged Following are the clinical signs of neurotrophic keratitis: epithelial cells desquamate and multiple erosions •• Presence of ciliary congestion. result, which produces characteristics punctate •• Decreased corneal sensation. Fluorescein staining (superficial punctate •• Persistent epithelial defects. The ulcer keratitis). is typically found in the interpalpebral Symptoms area, and the cornea appears dull. It is Symptoms include burning pain, lacrimation, followed by stromal edema and melting photophobia, and blepharospasm. (Flowchart 6.5).

Prophylaxis consists of wearing dark glasses Treatment made of crooks glass which cuts off nearly all •• Decreased aqueous tear production in infrared and UV rays. neurotrophic keratitis is treated with: •• Topical lubricant eye drops (preservative- Treatment free). Treatment includes cold compression, lubricant •• Punctal occlusion abolishes drainage of drops, and bandaging both eyes for a day. tears. •• Tarsorrhaphy to prevent drying and reduce ██ Trophic Keratitis exposure. It is a good alternative and kept for at least 1 year (OP4.7). Neurotrophic Keratitis •• Amniotic membrane transplantation. Sensory innervation is vital for the health of corneal epithelium and stroma. Neurotrophic Exposure Keratitis keratitis occurs in an anesthetic cornea, that is, it Lids resurface the cornea with the help of precor­ results from damage to the trigeminal nerve which neal tear film at each blink and keep the cornea supplies the cornea. Following are the causes of moist. Exposure keratitis is caused by improper neurotrophic keratitis: wetting of corneal surface by precorneal tear film despite the presence of normal tear secretions. 1. Damage to trigeminal nerve: It may occur due to surgery for trigeminal neuralgia, Etiology injection of alcohol in gasserian ganglion It is caused by the conditions that lead to exposure for trigeminal neuralgia, and tumors: of cornea, that is, due to incomplete closure of lids. acoustic neuroma and neurofibroma. Causes of exposure keratitis (lagophthalmos) are: 2. Ocular disease such as the following: 1. Facial nerve palsy (neuroparalytic •• Herpes simplex keratitis. keratitis): VIIth nerve palsy may be •• Herpes zoster keratitis. idiopathic or can follow surgery for 152 Chapter 6

Damage to ophthalmic division (1st division) of trigeminal nerve

Loss of neural reflex

Reflex tear secretion is reduced Altered metabolic activity of epithelial cells

Edema and exfoliation of epithelial cells

Epithelial breakdown and persistent ulceration

Flowchart 6.4 Pathogenesis of neurotrophic keratitis.

Trigeminal nerve damage (1st Decrease corneal sensation No pain division) in neurotrophic keratitis

Damage to lacrimal nerve (a branch Intracellular oedema due to of ophthalmic division of Vth CN) loss of neural influences and Cornea appears which supplies lacrimal gland exfoliation dull

Decreased aqueous tear production Persistent epithelial defect

Foreign body sensation Stromal edema and melting

Flowchart 6.5 Clinical features in neurotrophic keratitis.

acoustic neuroma/parotid tumor. It results Occasionally corneal exposure during sleep in the paralysis of orbicularis muscle and may occur in normal healthy individuals if there incomplete closure of lid. is poor Bell’s phenomenon. 2. Severe proptosis due to thyroid ophthal­ Pathogenesis mopathy and orbital tumor. 3. Eyelid scarring associated with cicatricial Incomplete closure of lids results in desiccation of pemphigoid, burns, and trauma. cornea. The epithelium is cast off, and invasion of 4. Reduced muscle tone as in coma. cornea by infective organisms may occur. The Cornea 153

Clinical Features feature. The lesion rapidly involves full-thickness Because of lagophthalmos, cornea is exposed of cornea. Finally, whole tissues undergo necrosis in lower part. So, initial desiccation occurs in and melt away (corneal melting by liquefactive the lower part of cornea, leading to inferior necrosis). punctate epithelial keratitis followed by epithelial Treatment breakdown, stromal melting, infection, and even Systemic treatment involves oral or IM adminis­ perforation (Fig. 6.21). tration of vitamin A. Locally, intense lubrication Treatment and topical antibiotics are advised. • • Tear substitutes (preservative-free lubri­ Atheromatous Corneal Ulcer cants) during day time. •• At night, application of eye ointment and It occurs in old leucoma undergoing degenerative closure of lids by tape or bandage. changes or it may start after a minor trauma. It •• Treatment of the cause of exposure, but is readily vulnerable to infection, as cornea is in the meantime, tarsorrhaphy may be devitalized and insensitive. It is treated with the required by suturing lids together (OP4.7). usual treatment, conjunctival flap, or keratoplasty. The amniotic membrane transplantation may be Combined neurotrophic (Vth CN damage) and neuro­ effective for the treatment of deep ulceration. paralytic (VIIth CN palsy) keratitis is difficult to manage. ██ Keratitis Associated with Skin Nutritional Deficiency (Vitamin A Diseases Deficiency) Rosacea Keratitis Ocular manifestations caused by vitamin A is a skin disease characterized deficiency are referred to as xerophthalmia. Acne rosacea by erythema of cheeks and nose in butterfly Cornea in vitamin A deficiency shows the configuration, progressing to telangiectasia, following changes: hypertrophy of sebaceous glands, papules and 1. Corneal xerosis: Earliest changes in pustules. Rosacea keratitis is usually associated cornea involve loss of corneal luster due with seborrheic blepharitis. It is generally seen to xerosis and bilateral punctate corneal among elderly women. epithelial erosions. 2. Keratomalacia: It reflects very severe vitamin A deficiency, often as early as the first year of life. Night blindness and conjunctival signs of vitamin A deficiency precede keratomalacia. The condition is usually bilateral. Bilateral melting of cornea is associated with conjunctival xerosis, and vitamin A deficiency is referred to as keratomalacia. In keratomalacia, cornea becomes dull, insensitive, and hazy. The ulcer is formed with yellow infiltrates. Typically, it is devoid of usual inflammatory reaction and is a characteristic Fig. 6.21 Exposure keratitis. 154 Chapter 6

Clinical Features trauma, chemicals, systemic diseases, or Symptoms include irritation, mild redness, and inflammation. • lacrimation. • Infiltration associated with lipid and mucopolysaccharide metabolisms. Clinical signs of rosacea keratitis are: •• Seborrheic blepharitis and recurrent ██ Arcus Senilis (Gerontoxon) chalazia. It is a lipid infiltration of peripheral corneal •• Conjunctival vessels in the interpalpebral stroma. It begins in the superior and inferior region are dilated. perilimbal cornea as a crescent and gradually •• Yellowish-white infiltrates are seen in the progresses circumferentially to form a circle. It cornea near the limbus which may ulcerate is approximately 1 mm wide and does not affect and then corneal vascularization takes vision. It is seen among the elderly population. place. It has a diffuse central border and a sharper •• Punctate epithelial keratopathy involving peripheral border. It is separated from limbus by lower cornea. a clear zone which is known as the lucid interval Treatment of Vogt.

Local treatment: Topical corticosteroids as drops or Arcus juvenilis (anterior embryotoxon): If ointment. the arcus appears in young persons (below 40 Systemic treatment: The essential treatment years of age), it is known as arcus juvenilis. It may involves treating the skin condition with systemic be associated with familial lipidemia. tetracycline 250 mg 4 times daily for 3 weeks and ██ then once daily for 6 months or doxycycline 100 Vogt Limbal Girdle mg twice daily for 3 weeks. It is an age-related change characterized by bilateral, chalky white crescentric lines in the ▄▄Corneal Degenerations (IM24.15) interpalpebral area along both nasal and temporal limbus. There is marked distinction between degeneration and dystrophy. Degenerations are nonhereditary ██ Hassell–Henle Bodies and usually unilateral, while dystrophies are hereditary and usually bilateral. These are the excrescences of hyaline material present in peripheral Descemet’s membrane and ██ Etiology are part of normal aging process. Degenerations could arise due to age-related ██ Terrien’s Marginal Degeneration changes like arcus senilis, Vogt limbal girdles and Hassell–Henle bodies or pathological changes like It is an idiopathic, noninflammatory thinning of lipid degenerations, amyloid degeneration, band peripheral cornea. It is usually bilateral, but may keratopathy, Salzmann’s nodular degeneration, be unilateral. It is more frequently seen in males. It Terrien’s marginal degeneration, and spheroidal is most frequent in middle-aged to elder persons. degeneration. Signs: It starts with fine yellow–white punctate stromal opacities and superficial vascularization,­ ██ Classification usually superiorly. The lesion spread circum­ Corneal degenerations can be divided into: ferentially and separated from the limbus by a •• Primary degenerations. clear zone. Progressive circumferential thinning •• Secondary degenerations due to some results in peripheral gutter. Astigmatism develops compromising factors, for example, from associated corneal flattening which may The Cornea 155 be irregular and results in visual deterioration. 4. Juvenile rheumatoid arthritis (Still’s Usually, there is no pain or inflammation. disease): Chronic uveitis in Still’s disease Perforation may rarely occur following blunt causes band-shaped keratopathy. trauma. 5. Chronic renal failure (CRF).

██ Band Shaped Keratopathy (Calcific Clinical Features Degeneration) Calcium is deposited as a horizontal band in the Band keratopathy is characterized by deposition interpalpebral area of the cornea. Calcification of calcium salts in the subepithelial layers starts near the corneal periphery which is (Bowman’s layer, epithelial basement membrane, separated from the limbus by a clear zone of and anterior stroma) of the cornea. Calcium is cornea as in so many degenerative conditions, deposited as hydroxyapatite salt. probably owing to better nutrition close to blood vessels. Calcium deposition gradually progresses Etiology toward the center to form a band-like chalky plaque (Fig. 6.22). The calcium plaque contains 1. Ocular causes: It occurs in eyes with clear holes where Bowman’s membrane is chronic diseases, particularly chronic traversed by nerve endings and the surface of this uveitis, glaucoma, chronic keratitis, opaque band appears stippled. Epithelium usually Pthisis bulbi, and silicone oil in anterior remains intact as deposition is beneath it. chamber, that is, in aphakic eyes which have undergone vitrectomy with silicone Treatment oil. It is indicated if the vision decreases or persistent 2. Increased serum calcium or phosphate. discomfort occurs. Central deposits may be 3. Systemic associations like sarcoidosis, removed by: hyperparathyroidism, vitamin D toxicity, •• Chelation—It involves removal of epithe­ and metastatic neoplasms to bone. All lium over deposits followed by application these conditions are associated with of 0.01 molar solution of EDTA (ethylene elevated serum calcium. diamine tetra acetic acid), which is a chelator of calcium. It removes most of the deposited calcium. Pad and bandage for reepithelialization is taken care of. •• Treat any underlying systemic conditions or persistent uveitis to prevent recurrences. •• PTK with excimer laser to remove band keratopathy. •• Lamellar keratoplasty may be performed.

██ Spheroidal Degeneration (Climatic Droplet Keratopathy) It is also called oil droplet keratopathy or actinic droplet keratopathy. Fig. 6.22 Band-shaped keratopathy. Source: Band- shaped keratopathy. In: Gulani A, ed. The art of Etiology pterygium surgery: mastering techniques and It is thought to be a result of UV light exposure and optimizing results. 1st Edition. Thieme; 2019. occurs most often in men who work outdoor in 156 Chapter 6 the sun and in areas that have sunlight reflection autosomal dominant except macular dystrophy off snow or sand. which has autosomal recessive inheritance.

Clinical Features ██ Classification It is always bilateral and characterized by the On the basis of corneal layer primarily involved, presence of subepithelial, golden or yellow, fine corneal dystrophies are classified into (Fig. 6.23). droplets in the interpalpebral area of peripheral •• Epithelial dystrophies: cornea and advance toward the center. Droplets šš Epithelial basement membrane appear oily although they are not of lipid origin. dystrophy. These globules are made up of a protein material šš Meesmann dystrophy. with elastotic features. As the condition advances, •• Bowman layer dystrophies: droplets become larger and form large corneal šš Reis-Buckler dystrophy. nodules with elevated corneal epithelium. šš Thiel-Behnke dystrophy. •• Stromal dystrophies: Treatment šš Lattice dystrophy. Majority of cases are asymptomatic. In cases with šš Granular dystrophy. central lesions affecting vision, PTK with excimer šš Macular dystrophy. laser or lamellar keratoplasty can be carried out. šš Gelatinous drop-like dystrophy. •• Endothelial dystrophies: ██ Salzmann Nodular Degeneration šš Fuch’s endothelial dystrophy. šš Posterior polymorphous dystrophy. Etiology šš Congenital hereditary endothelial It occurs in persons with previous chronic dystrophy. keratitis, particularly associated with trachoma, phlyctenular keratitis, vernal keratitis and IK. Epithelial Dystrophies

It is characterized by bluish-white, avascular Epithelial dystrophies include: nodules in superficial stroma and Bowman’s •• Epithelial basement membrane dystrophy membrane that elevate the epithelium and may (Cogan’s microcystic dystrophy or map-dot- be associated with recurrent corneal erosions. The fingerprint dystrophy). base of the nodule may be outlined by epithelial •• Meesmann’s dystrophy (juvenile epithelial iron deposits. dystrophy). Epithelial Basement Membrane Dystrophy Treatment Onset: In the second decade, the condition is Most of the cases are asymptomatic and require asymptomatic. In a few patients, recurrent corneal no treatment. If nodules encroach the central erosions develop in the third decade. cornea, affecting vision, PTK with excimer laser or Clinical features: It is characterized by lamellar keratoplasty can be done. bilateral, intraepithelial lesions which are best ▄▄Corneal Dystrophies (OP4.5) visualized by retroillumination. The pattern of lesions may be: dot-like opacities, epithelial Corneal dystrophies are a group of opacifying microcysts, fingerprint-like lines or map-like gray disorders of cornea which are progressive, bilateral, patches. Simultaneous bilateral recurrent corneal symmetrical, hereditary, non inflammatory erosions suggest epithelial basement membrane and nonvascularized. All corneal dystrophies are dystrophy. The Cornea 157

1. Epithelial Epitophies 2. Bowman layer dystrophies - Epithelial basement - Reis–Buckler dystrophy - membrane dystrophy - Thiel–Behnke dystrophy - Meesmann dystrophy

3. Stromal dystrophies - Lattice dystrophy - Granular dystrophy Descemet’s membrane - Macular dystrophy - Gelatinous drop-like dystrophy 4. Endothelial dystrophies - Fuch’s endothelial dystrophy - Posterior polymorphous dystrophy - Congenital hereditary endothelial dystrophy

Fig. 6.23 Classification of corneal dystrophies.

Histology: It shows thickening of basement Clinical features: These are characterized by membrane and deposition of fibrillar material gray–white, round opacities in the central cornea. between basement membrane and Bowman’s Over time, these result in a reticular pattern in the membrane. Reis–Buckler dystrophy and assume a honeycomb Meesmann’s Dystrophy (Juvenile Epithelial pattern in the Thiel–Behnke dystrophy. Patients Dystrophy) have recurrent corneal erosions which are painful initially. Later, the pain diminishes, as corneal Onset: It is in the first 2 years of life, and has sensitivity decreases. Vision is impaired due to autosomal dominant inheritance. fibrosis at Bowman’s layer. Clinical features: It is characterized by multiple, Histology: It shows destruction of Bowman’s tiny intraepithelial vesicles which are maximum membrane and fibrous tissue, replacing Bowman’s centrally. The patient remains asymptomatic layer in both dystrophies. until middle age, then vesicles break through the : Symptomatic for . anterior epithelial surface and cause intermittent Treatment recurrent erosions Excimer laser keratectomy for visual disturbance. irritation and decrease in visual acuity. Corneal Lamellar keratoplasty is associated with relatively sensations are reduced. rapid recurrence of dystrophy on the graft and Bowman Layer Dystrophies penetrating keratoplasty (PKP) may become necessary in both dystrophies. These include: •• Reis–Buckler dystrophy (corneal dystro­ Stromal Corneal Dystrophies phy of Bowman’s layer type I or granular •• These include: Granular corneal dystrophy. corneal dystrophy). •• Macular corneal dystrophy. •• Thiel–Behnke dystrophy (Honey comb •• Lattice corneal dystrophy. dystrophy or corneal dystrophy of •• Schnyder crystalline dystrophy. Bowman’s membrane Type II). Granular Dystrophy Characteristics of both types of Bowman layer dystrophies: Inheritance: Autosomal dominant.

Inheritance: Autosomal dominant. Onset: In first decade of life. 158 Chapter 6

Clinical features: Opacities are dense, white and Treatment: Penetrating keratoplasty is indicated granular in the anterior stroma of central cornea, but recurrence in graft may occur. sparing the peripheral cornea. The intervening Lattice Dystrophy cornea between the opacities also remains clear (Fig. 6.24). Inheritance: Autosomal dominant. Histopathology: The opacities are formed due to Onset: During the second decade. the hyaline degeneration of collagenous protein Clinical features: It is characterized by presence and stain with Masson trichrome. of branched, crisscross lines along with punctate Effect on vision: Glare is present but the vision is opacities in between. good. The opacities coalesce into various irregular Histopathology: Histopathology reveals that it is shapes and vision is impaired. a form of amyloidosis, that is, amyloid is deposited Treatment: PKP is usually required by the fifth in the corneal stroma and stain with Congo red. decade. Effect on vision: The crisscross lines form an Macular Dystrophy irregular lattice work and cause impairment of visual acuity. Inheritance: Autosomal recessive. Treatment: PKP is the treatment of choice when Onset: In the first decade of life (6–9 years). acuity decreases significantly. Clinical features: Opacities assume a discrete Schnyder Crystalline Dystrophy granular form in the central cornea which spreads It is a disorder of corneal lipid metabolism to the periphery. There is no clear space between associated with systemic hypercholesterolemia the opacities. (raised serum cholesterol). Histopathology: The opacities are composed of Inheritance: Autosomal dominant. glycosaminoglycans (GAG) and stain with alcian blue. Features: It is caused by central subepithelial corneal crystals, often in a ring pattern, initially Effect on vision: Vision is affected at an early age. in the first decade of life. With advancing age, central corneal haze becomes evident.

Histology: Shows accumulation of cholesterol and phospholipids throughout stroma.

Treatment: Excimer laser keratectomy is advised.

Endothelial Corneal Dystrophies •• These include: Fuch’s endothelial dystrophy. •• Posterior polymorphous dystrophy. Fuch’s Endothelial Dystrophy It is bilateral and associated with increased incidence of primary open-angle glaucoma. Granular dystrophy. Source: Corneal dis­ Fig. 6.24 Inheritance: It is autosomal dominant. orders. In: Narang P, Trattler W, ed. Optimizing sub­ Age: It occurs after 50 years. optimal results following cataract surgery. 1st Edition. Thieme; 2018. Sex: It is more common in females. The Cornea 159

Stagings: It is characterized by progressive loss Patient complains of blurred vision in morning of corneal endothelial cells, resulting in reduced that improves during the day, Glare and colored vision, and the severity of disease varies as follows halos around lights in the morning. ( ): Flowchart 6.6 Stage 3: Due to progressive endothelial Stage 1: Earliest finding in Fuch’s dystrophy is decompensation, epithelial edema with bullae the presence of excrescences (irregular warts) of formation takes place (bullous keratopathy). The Descemet’s membrane called guttae in the central periodic rupture of bullae causes: corneal endothelium (corneal guttata) which •• Pain and discomfort due to exposure of involve the corneal periphery as well with time. naked nerve endings, and eye is prone to The confluence of guttae produces a roughened secondary infection. surface with beaten metal appearance. Stroma •• Profound reduction in vision. and epithelium are uninvolved and patient’s Diagnosis—It is diagnosed by: vision is normal at this stage. •• Specular microscopy: It is done for Stage 2: Disruption of normal endothelial mosaic endothelial cell count (Fig. 6.25). takes place with endothelial dysfunction. It •• Corneal pachymetry: It is done to document results in stromal edema which is significant increased corneal thickness. upon awakening and clears later in the day due to •• Confocal microscopy: It is done to image evaporation. Stromal edema results in Descemet endothelium in the presence of corneal membrane’s folds with increase in corneal edema (corneal opacification precludes thickness. specular microscopy).

Corneal guttata (excrescences of Descemet’s membrane)

Stage 1 Beaten metal appearance due to confluence of guttae— vision is normal at this stage

Disruption of normal endothelial mosaic • Blurred vision Stage 2 in morning • Glare Endothelial dysfunction with stromal edema • Coloured halos

Progressive endothelial decompensation

• Pain and Stage 3 Epithelial oedema with bullae formation discomfort • Profound Rupture of bullae reduction in vision

Flowchart 6.6 Staging of Fuch’s endothelial dystrophy. 160 Chapter 6

a b c

Fig. 6.25 Fuch’s dystrophy. (a) On slit lamp. Source: History. In: Singh K, Smiddy W, Lee A, ed. Ophthalmology review: a case-study approach. 2nd Edition. Thieme; 2018. (b) Moderate type. (c) Advanced type with endotheliopathy (on specular biomicroscopy). Source: Specular microscopy and pachymetry. In: Narang P, Trattler W, ed. Optimizing suboptimal results following cataract surgery. 1st Edition. Thieme; 2018.

Differential diagnosis—It includes: •• Posterior polymorphous dystrophy. •• Congenital hereditary endothelial dystrophy. •• Aphakic/pseudophakic bullous keratopathy (Fig. 6.26). •• Hassell–Henle bodies.

Treatment •• Topical Sodium Chloride as drops (5%) and ointment (6%). •• Lubricating eye drops. •• Bandage contact lenses to relieve pain caused by rupture of bullae. •• PKP. •• If IOP is >20 mm Hg, reduce it. Lowering of Fig. 6.26 Pseudophakic bullous keratopathy. IOP may reduce the force that drives the fluid into stroma. Posterior Polymorphous Dystrophy Cataract surgery and Fuch’s endothelial dystrophy Cataract surgery may accelerate endothelial cell loss. Inheritance: Usually autosomal dominant. Extra precautions during intraocular surgery (such as intraoperative soft shell viscoelastics technique) should Clinical features: It occurs early in life and is be taken to protect the endothelium from surgical characterized by the presence of multilayered trauma: •• In eye with corneal epithelial edema or corneal endothelium. The single cell layer of endothelium thickness >640 µm by pachymetery, consider is transformed into a multilayered epithelium- triple procedure, that is, cataract surgery + IOL implantation + keratoplasty. like tissue. The posterior surface of cornea shows •• If corneal thickness is <640 µm, good visual outcome vesicular pattern, band-like lesions of diffuse is expected. opacities. The Cornea 161

Treatment the margin of cone is seen in red reflex “oil It is usually asymptomatic and treatment is droplet” reflex which alters its position on not required. Those with corneal opacification moving the ophthalmoscope (Fig. 6.27b). require PKP. •• Retinoscopy shows irregular “scissor” reflex. ▄▄Ectatic Conditions of Cornea •• A ring of iron deposition occurs in the epithelium at the base of cone (Fleischer Disorders of corneal shape include: ring). It is best seen with a cobalt-blue filter. •• Keratoconus. •• Presence of vertical striae in deep stroma •• Keratoglobus. (Vogt striae) may be noticed. These deep •• Pellucid marginal degeneration. stromal stress lines disappear with external ██ Keratoconus (Conical Cornea) pressure on the globe (Fig. 6.27c). (OP4.5) •• Distortion of corneal reflex is best seen with Placido disc or corneal topography. It is a progressive steepening of cornea secondary •• When light beam is focused from the to stromal thinning whereby it assumes a conical temporal side across the cornea, a conical shape. The apex of cone always being slightly reflection is seen on the nasal cornea below the center of cornea. It occurs around pub­ (Rizutti’s sign). erty with slow progression. It is usually bilateral but the patients have asymmetrical involvement. Sometimes, rupture in Descemet’s membrane develops, which causes influx of aqueous into Etiology cornea (acute hydrops) and sudden stromal edema with opacification. It results in sudden It is unknown but seems to be multifactorial. It impairment of visual acuity. Break usually heals may be: within 6 to 10 weeks, corneal edema clears, and •• Due to congenital weakness of the cornea. stromal scarring may develop. •• Secondary to trauma. •• Associated with Down syndrome. Keratoconus can be graded by keratometry, as •• Due to repeated rubbing of the eyes. depicted in Table 6.12.

Clinical Features Associations Symptoms include progressive bulging of Systemic associations: Keratoconus may be asso­ cornea which induces myopic astigmatism and ciated with: subsequently becomes irregular. It causes marked •• Down’s syndrome. visual impairment and the patient may complain •• Marfan’s syndrome. of frequent changes in spectacle power and •• Ehlers Danlos syndrome. decreased tolerance to contact lens wear. •• Apert’s syndrome. •• Atopy. Ocular manifestations of keratoconus are limited to cornea and include: Ocular associations—These include: •• Conical protrusion of cornea with apex of •• Vernal keratoconjunctivitis. cone slightly below the center of cornea •• Leber’s congenital amaurosis. (Fig. 6.27a). •• Retinopathy of prematurity. •• Bulging of lower eyelid by cone of cornea on •• Fuch’s dystrophy. down gaze (Munson’s sign). •• Blue sclera. •• With direct ophthalmoscope at 1 m •• Aniridia. distance, a ring of shadow concentric with •• Ectopia lentis. 162 Chapter 6

a b

Fig. 6.27 (a) Conical protru­sion of cornea. (b) Oil droplet red reflex. (c) Vogt’s striae. Source: History. In: Singh K, Smiddy W, Lee A, ed. Ophthalmology review: A case-study c approach. 2nd edition. Thieme; 2018.

Posterior keratoconus Table 6.12 Grading of keratoconus In posterior keratoconus, the posterior corneal surface protrudes into the stroma. Frequently, scarring occurs Grade of keratoconus Keratometry reading in stroma, anterior to Descemet’s bulge. It is congenital, Mild < 48 D nonprogressive, and usually unilateral. Moderate 48–54 D Treatment Severe > 54 D •• Spectacles in early stages to correct refractive errors. cross-linking of corneal collagen fibrils by •• Rigid gas permeable contact lenses to formation of intrafibrillary and interfibrillar eliminate irregular corneal curvature. So, covalent bonds and stabilizes the corneal these are required to correct higher degree stroma. Bandage soft contact lenses are of astigmatism. prescribed to permit the epithelium to heal. •• Intracorneal rings in low to moderate •• Corneal transplantation (Keratoplasty): keratoconus. It is done if disease progresses despite all •• Corneal collagen cross linking (CCC): It measures and in case of acute hydrops. is a new technique to arrest progression PKP or deep lamellar keratoplasty is currently of keratoconus. In this procedure, corneal becoming procedure of choice. It removes entire epithelial is removed and riboflavin 0.1% eye corneal stroma, sparing the host’s Descemet drops are instilled over cornea till cornea is membrane and endothelium. It reduces the adequately saturated, which is exposed to risk of rejection and the donor cornea with low UV radiation. Riboflavin triggers increased endothelial cell count can be used. The Cornea 163

Table 6.13 Differentiating features between keratoglobus and buphthalmos

Keratoglobus Buphthalmos

Corneal transparency Clear cornea Hazy IOP Normal Increased Angle of anterior chamber Normal Angle anomaly present Optic disc No cupping Cupping present

Abbreviation: IOP, intraocular pressure.

██ Keratoglobus •• Area of thinning is 1 to 2 mm inside the inferior limbus and measures approximately It is congenital, nonprogressive, and bilateral. It 2 mm in width and 6 to 8 mm in horizontal is inherited as an autosomal recessive trait. It is extent (4–8 o’clock). characterized by hemispherical (globular) corneal •• Cornea above the crescent-shaped band protrusion due to thinning of entire cornea (i.e., of thinning protrudes with flattening in limbus-to-limbus corneal thinning). In contrast, vertical meridian. Therefore, there is a keratoconus shows central stromal thinning. marked against-the-rule astigmatism and It may be associated with blue sclera and systemic reduced visual acuity. connective tissue abnormalities. Vogt striae and •• Epithelium is intact. Fleischer’s ring are absent. It must be differentiated •• Vogt striae (deep stromal stress lines) and from buphthalmos (Table 6.13). Fleischer’s ring do not occur. Corneal topography shows generalized •• Acute hydrops is rare. steepening, and cornea is more prone to rupture •• Corneal topography shows a classical on relatively mild trauma in keratoglobus. It is “butterfly” pattern. treated with scleral contact lenses because results of surgery are very poor. Treatment •• Contact lenses are prescribed for correction ██ Pellucid Marginal Degeneration of astigmatism. Spectacles usually fail due It is a progressive, bilateral peripheral corneal to increasing irregular astigmatism. thinning typically affecting the inferior cornea •• Surgery includes: (usually 4 to 8 o’clock positions). šš Large eccentric penetrating keratoplasty. The following clinical signs helps in diagnosing šš Crescentric lamellar keratoplasty. pellucid marginal degeneration: šš Thermocauterization.